Abstract
Astrocytes comprise half of the cells in the central nervous system and play a critical role in maintaining metabolic homeostasis. Metabolic dysfunction in astrocytes has been indicated as the primary cause of neurological diseases, such as depression, Alzheimer’s disease, and epilepsy. Although the metabolic functionalities of astrocytes are well known, their relationship to neurological disorders is poorly understood. The ways in which astrocytes regulate the metabolism of glucose, amino acids, and lipids have all been implicated in neurological diseases. Metabolism in astrocytes has also exhibited a significant influence on neuron functionality and the brain’s neuro-network. In this review, we focused on metabolic processes present in astrocytes, most notably the glucose metabolic pathway, the fatty acid metabolic pathway, and the amino-acid metabolic pathway. For glucose metabolism, we focused on the glycolysis pathway, pentose-phosphate pathway, and oxidative phosphorylation pathway. In fatty acid metabolism, we followed fatty acid oxidation, ketone body metabolism, and sphingolipid metabolism. For amino acid metabolism, we summarized neurotransmitter metabolism and the serine and kynurenine metabolic pathways. This review will provide an overview of functional changes in astrocyte metabolism and provide an overall perspective of current treatment and therapy for neurological disorders.
1. Introduction
Astrocytes are remarkably multifunctional cells, and most of their functions are closely connected with neurons in the brain. Astrocytes form a functional syncytial network via their gap junctions and play important homeostatic roles in the central nervous system (). This connection allows for intercellular communication of neurons and astrocytes through various mechanisms, including both chemical and synaptic transmissions (Lines et al., 2020; Shan et al., 2021). Once cast as a supporting role for neurons, recent advances have slowly shifted the views of astrocytes to a more central role. Astrocytes have been found to undergo various changes ranging from hypertrophy, atrophy, or cell death in response to injury and neurological disorders (Verkhratsky et al., 2017b; ). These morphological changes during neurological disorders may alter astrocytic metabolism (). Recent studies have highlighted the significant impact of astrocyte metabolism on neurological disorders (Muddapu et al., 2020). However, the causal link between astrocytic metabolic dysregulation and the onset of various neurological disorders remains elusive (Phatnani and Maniatis, 2015). In this review, we explore the morphology and functionality of astrocytes, as well as the metabolic alterations they undergo in the context of neurological disorders such as depression, Alzheimer’s disease (AD), and epilepsy. Our goal is to offer innovative perspectives that can guide future research in this field.
2. Astrocyte morphology and functionality in the brain
Astrocytes exhibit various morphologies, such as star-shaped, bushy, and spongiform structures, which exist in the brain and spinal cord (Pathak and Sriram, 2023b). However, there are currently controversies over the total number of astrocytes and their proportions in different brain regions. It is estimated that astrocytes make up almost 40% of all cells in the human brain, with variations in different brain regions (Sherwood et al., 2006; von Bartheld et al., 2016). Astrocytes in the CNS are divided into four morphological types: protoplasmic, fibrous, varicose, and interlaminar (; Rasmussen and Smith, 2022). Protoplasmic astrocytes possess bushy processes and exist primarily in the gray matter. These protoplasmic astrocyte processes extend to the blood vessels, forming a connective membrane that connects to the blood brain barrier (BBB; Jackson et al., 2022). Protoplasmic astrocytes have various functions, including modulation of synaptic function, clearance of glutamate, regulation of blood flowrate, and participation in synaptogenesis (). In contrast, fibrous astrocytes possess long extending processes and are typically distributed in the white matter (Sartoretti and Campetella, 2022). Varicose projection and interlaminar astrocytes are only observed in humans and chimpanzees (). Interlaminar astrocytes connect to neurons, pia, and capillaries, suggesting roles such as cortical neuron communication, and may play an essential role in the BBB ().
The special cytoarchitectural and quantitative features of astrocytes make them play an important role in different metabolic pathways. Structurally, astrocytes are distributed around blood vessels and neurons in the brain, connecting the periphery and the brain for energy exchange and acting as a bridge for communication between cells (; Yue and Hoi, 2023). Regarding glucose metabolism, astrocytes are a primary site for glycolysis and provide neurons with glycogen and lactate, and the astrocyte-neuron lactate shuttle model (ANLS) is critical for neuronal activity (Herrera Moro Chao et al., 2022). Moreover, astrocytes participate in maintaining pathways of amino acid metabolism, fatty acid metabolism, ion and water homeostasis, defense against oxidative stress, and anti-inflammation (Sofroniew, 2020). Changes in these astrocytic pathways also influence the activity of neurons and may lead to neurological disorders (; Patani et al., 2023; Yao et al., 2023).
3. Glucose metabolism
3.1. Astrocytes and the glucose metabolism pathway: main energy source of the brain
Astrocytes metabolize glucose from the bloodstream to fuel surrounding neurons (Figure 1). Glucose is regulated mainly by glucose transporters (GLUT; Mergenthaler et al., 2013). These transporters, such as GLUT1 and GLUT3, are abundant in astrocytes and neurons, respectively, while astrocytes show limited GLUT2 expression (Koepsell, 2020; Figure 1A). There are currently two types of GLUT1 isoforms. The first GLUT1 isoform is the 55-kDa isoform, which is located in the endothelial cells that form the BBB (Kreft et al., 2012). Glucose enters astrocytes from the interstitium via the 45-kDa isoform of GLUT1 and into neurons via GLUT3, a neuronal GLUT (Kreft et al., 2012). GLUT 1 transporters are located in the astrocyte cell body and foot processes, which shuttle glucose from the bloodstream across the BBB into astrocytes (Nguyen et al., 2021). GLUT3 is located in the neural foot processes and transports glucose into neurons. Following its entry into the cell, glucose undergoes phosphorylation, a process catalyzed by hexokinase type I, which is ubiquitous in the brain and closely associated with mitochondria (Koepsell, 2020). Hexokinase type I migrates from mitochondria to microtubules during gap junction inhibition, inducing the expression of hexokinase type II and GLUT3, which are normally not present in astrocytes (Sánchez-Alvarez et al., 2004). Postphosphorylation, glucose becomes glucose-6-phosphate (G6P), which then enters either glycolysis or the pentose-phosphate pathway (PPP; Takahashi, 2021). During glycolysis, G6P is converted into fructose-6-phosphate (F6P) by phosphohexose isomerase and subsequently phosphorylated by phosphofructokinase to yield fructose 1,6-bisphosphate (F1,6-bisP). Aldolase then cleaves F1,6-bisP to generate glyceraldehyde 3-phosphate (Gly3-P) and dihydroxyacetone phosphate (DHAP), which can be interconverted by phosphotriose isomerase. Gly3-P undergoes conversion into 1,3-bisphosphoglycerate (1,3-bisPG) through a process catalyzed by nicotinamide adenine dinucleotide (NAD)-dependent dehydrogenase and is then phosphorylated by phosphoglycerate kinase into 3-phosphoglycerate (3-PG). 3-PG is dephosphorylated to form 2-phosphogylcerate by phosphoglycerate mutase and subsequently dehydrated by enolase into phosphoenolpyruvate. Phosphoenolpyruvate is phosphorylated by pyruvate kinase into pyruvate, which can then enter the Krebs cycle or be converted to lactate. Both of these routes can generate NADH that can be used for continuous glycolysis, the former being more complicated due to transport out of the mitochondria (Kumari, 2018). Alternatively, pyruvate can be converted into acetyl-coenzyme A (acetyl-CoA) by the pyruvate dehydrogenase complex, serving as a precursor for the synthesis of amino acids, phospholipids, ketone bodies, and other substrates (Shi and Tu, 2015). Glucose metabolism in astrocytes provides the necessary metabolic substrate to respond to the energy needs of neurons, ensuring their normal functions.
Figure 1
Another pathway for G6P is the PPP pathway, which accounts for approximately 3% of glucose metabolism (Figure 1B; Takahashi, 2021). The PPP is a shunt pathway split into two phases: oxidative and nonoxidative (Kamada et al., 2003). The oxidative phase generates ribulose-5-phosphate (R5P) through G6P dehydrogenase and assists in neutralizing radical oxygen species (ROS; Wamelink et al., 2008; Takahashi, 2021). Meanwhile, in the nonoxidative phase, R5P can be isomerized into ribose-5-phosphate and used for nucleotide biosynthesis (Wamelink et al., 2008). Additionally, R5P can be converted into glyceraldehyde-3-phosphate and fructose-6-phosphate (F6P), with the latter being able to isomerize back to G6P (Wamelink et al., 2008). The PPP has been identified as a mechanism for protecting neurons from oxidative stress (). Interestingly, the rate of glucose entry into the PPP in astrocytes is five to seven times higher than that in neurons, reflecting astrocytes’ higher glycolytic rate (Takahashi, 2021). Under hypoxic conditions, the rate of glucose flux into the PPP in astrocytes is elevated, while PPP activity is decreased in cultured neurons (Takahashi, 2021). These observations underscore the critical role that astrocytes play under hypoxic conditions, providing antioxidant defense for neurons to help prevent neuronal cell death.
In situations of glucose availability, G6P is shunted into glycogen storage via conversion into glycogen by glycogen-synthase for later use (Wender et al., 2000). When astrocytes or neurons require energy, glycogen phosphorylase can revert glycogen back into G6P, allowing it to reenter glycolysis (Nadeau et al., 2018). Notably, astrocytic glycogen is not uniformly distributed, and research suggests that it tends to accumulate in areas of the brain with the highest synaptic density (Phelps, 1972). This finding indicates that glycogen may play a role in synaptic functionality. However, subsequent research has revealed significant glycogen concentrations in the white matter as well, which does not contain synapses (). Given that the white matter region consists of glial cells and is devoid of neurons, glycogen stored in this region may serve a supportive role for myelin or function as storage. Early research primarily considered glycogen as a safeguard against hypoglycemia, providing the brain with energy during periods of low glucose or when the glucose present in the blood is insufficient to meet increased energy demand ().
Recent research has unveiled the versatile role of glycogen in the brain’s energy dynamics. It has been discovered that glycogen can be converted to lactate, power glutamate transport, and contribute to the synthesis of glutamine, a precursor to glutamate, a key neurotransmitter essential for neuronal communication (; ). These findings imply that glycogen may have a significant and multifaceted role in neuronal modulation through the process of glycogenolysis. Moreover, this implies that glycogen can be converted into other energy substrates, such as glucose and lactate, whenever necessary for maintaining brain functionality.
3.2. Astrocytes and lactate: functionality in neuronal regulation
In astrocytes, lactate is generated as a byproduct of glycolysis. Lactate is a critical energy substrate produced by astrocytes during neuronal activity (Figure 1C; Roberts and Chih, 2003; Xue et al., 2022). One hypothesis suggests that the synaptic release of glutamate can trigger glycolytic production of lactate in astrocytes. The lactate produced is then released extracellularly and taken up by surrounding neurons to fuel oxidative metabolism during activity (Pellerin and Magistretti, 1994). This hypothesis was indirectly supported by the distribution of lactate dehydrogenase isoforms in activity-dependent astrocytes (Pellerin et al., 1998). However, PET measurements of cerebral oxygen consumption in the brain suggest that neurons increase their oxidative metabolism in parallel with an increase in pyruvate (Kasischke, 2009). This implies that glycolysis in neurons, not astrocytes, determines the kinetics of the metabolic response. More recent research found that lactate can act as a viable energy source and increase in the brain during neuronal activity, suggesting that it may replace glucose as the primary energy source for neurons (Wyss et al., 2011). Additionally, lactate produced from glucose or glycogen in astrocytes can be transferred via monocarboxylic acid transporters (MCTs) from astrocytes to neurons or so-called ANLS (Magistretti and Allaman, 2018; Yamagata, 2022). It is theorized that these shuttles shift between astrocytes, providing neurons with the necessary energy for normal operations. However, whether neurons prefer lactate over glucose remains undetermined. Lactate is released by astrocytes through MCTs into the extracellular matrix, from which it may be transported into neurons via MCTs present on neurons or passively through gap junctions (; Yamagata, 2022). It is theorized that astrocytes only release lactate to neurons during periods of low energy or as a supplementary energy source during neuronal activity, as suggested by research studies (; Magistretti and Allaman, 2018). Once lactate enters the neurons, it is converted back into pyruvate and transported into the mitochondria to generate ATP ().
Although there have been theories on whether neurons require lactate as an energy source, Mangia et al. showed that neurons export lactate and astrocytes import lactate and for enabling astrocytes to export lactate, the glucose transport capacity of astrocytes must be increased 12-fold and that glucose must not respond to activation with increased glycolysis (Mangia et al., 2009). Furthermore, in a more recent study, Diaz-Carcia et al. measured the neuronal NADH/NAD+ ratio by employing a biosensor during stimulation and found that neurons upregulate glycolysis more than oxidation and release lactate (). These findings indicate that activated neurons do not depend on extracellular lactate for neuronal function, which questions the theory of ANLS at the cellular level (). Although extracellular lactate is not used for energy supplementation for neuronal firing, there may be other functionalities of lactate in the brain. For instance, astrocytes have recently been found to contribute to memory formation (Kol et al., 2020) and employ lactate in influencing memory or cognitive behaviors. Recent studies have revealed that lactate production in astrocytes expresses β2 adrenergic receptors (β2AR), which are integral for memory consolidation (). Furthermore, disruption of the astrocyte-neuron lactate shuttle was found to impair the formation of long-term memory (Lindberg et al., 2019). These findings underscore the importance of lactate production by astrocytes and its influence on cognitive functions. Lactate was also found to signal through specific G-protein coupled receptors expressed in neurons and glial cells, suggesting a possible role in neurotransmission, neurovascular coupling, and brain energy metabolism (Morland et al., 2015).
3.3. Oxidative phosphorylation pathway: mitochondrial metabolism in astrocytes
The oxidative phosphorylation pathway is present in both astrocytes and neurons. Although this pathway is more prominent in neurons, astrocytes utilize oxidative phosphorylation to protect neurons against oxidative stress by providing neurons with a reduced form of glutathione (Takahashi, 2021; Figure 1D). This pathway takes place in the cell’s mitochondria and is vital for maintaining cellular functionality. The mitochondrion, a small organelle in the cell responsible for energy generation, is found in the processes of astrocytes (Jackson and Robinson, 2018). The pyruvate generated from glycolysis is actively transported into the mitochondria via mitochondrial pyruvate carrier 1 (Rose et al., 2020). Pyruvate undergoes oxidative decarboxylation, forming acetyl-CoA, which then enters the tricarboxylic acid (TCA) cycle. Upon reacting with oxaloacetate, citrate is formed, and a series of oxidation reactions generate ATP (Rose et al., 2020). Although the oxidative phosphorylation pathway can produce energy in times of stress to aid in the survival of astrocytes and neurons, other pathways have also been found to be capable of sustaining astrocyte survival in the event of mitochondrial inhibition (San Martin et al., 2017). This activates 5’-AMP-activated protein kinase (AMPK) to upregulate the glycolysis of 6-phosphofructo-1-kinase (PFK1), which compensates for the loss of mitochondrial ATP and maintains the mitochondrial membrane potential (). During times of low energy production, such as under ischemic conditions, metabolic shifts occur from neurons to astrocytes to preserve energy due to the lower energy demand of astrocytes compared to neurons (). Liang et al. found that GLUT3 presents unique Michaelis–Menten characteristics of low Km and high Vmax, indicating that GLUT3 can uptake glucose from the extracellular fluid of low glucose concentration by the highest possible maximum velocity (Liang and Bourdon, 2018). Therefore, GLUT3 on neurons is beneficial for glucose uptake at low glucose concentrations in the brain. In this condition, the glucose concentration of the brain parenchyma was maintained at 1–2 mM. Inhibition of the oxidative phosphorylation pathway in neurons can lead to cell death because glycolysis in neurons cannot be activated to the same extent as in astrocytes (). This activation of glycolysis is partially due to the presence of 6-phosphofructose-2-kinase/fructose-2,6-bisphosphatase-3 (PFKFB3), a key enzyme promoting glycolysis (). Nonetheless, the oxidative phosphorylation pathway is essential in providing energy for both astrocytes and neurons, ensuring neuronal survival and maintaining functionality ().
4. Fat and lipid metabolism
4.1. Astrocytes and fatty acid metabolism
Astrocytes are the main sites for fatty acid oxidation in the brain (). During energy deficits, fatty acid oxidation and ketone body production are essential in the brain as an alternate source of energy for maintaining normal brain functions (Figure 2; Le Foll and Levin, 2016). Fatty acids can help support the TCA cycle and oxidative phosphorylation in astrocytes (Panov et al., 2014). In the TCA cycle, α-ketoglutarate is converted into succinyl CoA through ketoglutarate dehydrogenase, after which the coenzyme is removed through succinyl CoA synthetase to form succinate. The formation of succinate and CoA allows for the phosphorylation of GDP to GTP.
Figure 2
4.2. Astrocytes and ketogenic metabolism
Astrocytes have the capacity to take up, synthesize, and release β-hydroxybutyrate (BHB; Le Foll and Levin, 2016). Astrocytes are the only source of ketone body (KB) production in the brain (Figure 2; Le Foll and Levin, 2016). One way for the brain to obtain KBs is from the BBB through monocarboxylate transporter 1 (MCT1) in endothelial cells, oligodendrocytes, and astrocytes. The liver supplies most of the KBs in the BBB and are oxidized by the brain when circulating glucose becomes scarce. Particular conditions, including prolonged fasting, uncontrolled diabetes, and breastfed newborn babies, increase circulating BHB and acetoacetate (Jensen et al., 2020). In such cases, the brain slowly adapts to the use of KBs to preserve neuronal synaptic function and structural stability. In the ketogenic synthetic pathway of astrocytes, fatty acids are transported into the mitochondria and then converted into acetyl-CoA through the β-oxidation cycle. Two acetyl-CoAs are then converted into acetoacetyl-CoA through acetyl coenzyme A acetyltransferase (ACAT). Acetoacetyl-CoA is then converted to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA), followed by acetoacetate, and finally, β-hydroxybutyrate (BHB) is supplied as a substrate for neuronal ATP synthesis. Astrocytes and, more recently, oligodendrocytes have been found to express MCT1 (Lee et al., 2012). MCT1 expression was found to be higher in oligodendrocytes than in astrocytes (Lee et al., 2012). Neurons almost exclusively express the MCT2 isoform, which possesses a high affinity for BHB released from endothelial cells and astrocytes. Acetoacetate and BHB are two ketone bodies used for energy when glucose levels decrease in neurons. Upon entering neurons, BHB can be converted to acetoacetate via β-hydroxybutyrate dehydrogenase, which is then converted back to acetyl-CoA via β-ketoacyl-CoA transferase, which subsequently enters the TCA cycle (). An interesting study investigating substrate oxidative metabolism in brain cellular models showed that oxidation of KBs by neurons and oligodendrocytes is three times more efficient than that by astrocytes ().
In addition to serving as an energy supply, KBs also serve as substrates for the production of lipids in the brain, such as myelin (). A study reported that ketone bodies protect myelin-forming oligodendrocytes and reduce axonal damage (Mu et al., 2022). Moreover, KBs can also act as posttranslational modification proteins to activate intracellular signaling pathways (Koppel and Swerdlow, 2018). Research has found that MCT2 expressed in neurons is mainly colocalized to mitochondria-rich postsynaptic density structures, suggesting that KBs play an important role in synaptic transmission (Pierre et al., 2002). Neurotransmitters released by neurons during enhanced synaptic activity may interact with astrocytes, stimulating the production of lactate and ketones for cellular activity (Guzman and Blazquez, 2001). Studies have shown that glutamate can enhance ketogenesis in cultured astrocytes, a process dependent on glutamate transporters (Guzman and Blazquez, 2004). Further research has found that ketones can modulate neuronal firing by opening ATP-sensitive calcium channels (Ma et al., 2007). This indicates the significant role of ketones in regulating neuronal activity, which might explain why a ketogenic diet is an effective treatment for epilepsy and other neurological disorders.
4.3. Sphingolipid metabolism: astrocytic regulation of neuron metabolism
Sphingolipid metabolism, although occupying a relatively small part of metabolism, plays an essential role in the brain. These sphingolipids are critical components in the formation of myelin sheaths. The biosynthesis of sphingolipids entails the conversion of L-serine and palmitoyl-CoA into ceramide, which is a crucial substrate for the generation of other sphingolipids, such as ceramide-1-phosphate (C1P) and sphingosine. Sphingosine can then be further converted into sphingosine-1-phosphate (S1P; Pralhada Rao et al., 2013). Both ceramide and sphingosine are vital regulators of stress responses, possessing the capability to inhibit cellular proliferation and mediate apoptosis, growth arrest, senescence, and differentiation (Pralhada Rao et al., 2013). On the other hand, S1P presents contrasting functionality to its unphosphorylated counterpart by promoting cell proliferation, migration, angiogenesis, and cell survival (Zeidan and Hannun, 2007). Early research has identified the critical role of sphingolipids in brain development and neuron survival (Hirabayashi and Furuya, 2008). Moreover, sphingolipid metabolism might also be instrumental in regulating astrocytic metabolic support for neurons (Lee et al., 2022). Given that these glycoproteins possess numerous essential functions for maintaining astrocyte and neuron stability within the brain, they represent an important factor to consider in the study and treatment of neurological disorders.
5. Amino acid metabolism in astrocytes
5.1. The glutamate/GABA-glutamine cycle
Similar to the energy metabolic pathways, the amino acid metabolic pathway in astrocytes plays an instrumental role in modulating brain functionality. Astrocyte metabolism is closely connected with the glutamate/GABA-glutamine cycle in neurons and helps regulate neurotransmitter homeostasis (). Astrocytes can take up synaptically released neurotransmitters, such as glutamate and γ-aminobutyric acid (GABA), and metabolize them into glutamine, which returns to neurons (). Glutamate is essential for synaptic functionality within the brain and is also identified as a precursor for GABA (Roberts and Frankel, 1950). The exchange of glutamate, GABA, and glutamine between neurons and astrocytes is known as the glutamate/GABA-glutamine cycle, which is crucial for maintaining excitatory and inhibitory neurotransmission ().
Importantly, efficient synaptic glutamate uptake, which is mainly transported by glutamate transporters of brain excitatory amino acid transporter 1 (EAAT1) and EAAT2 in astrocytes, is vital to avoid excitatory overstimulation and concurrent excitotoxic damage (Storck et al., 1992; Petr et al., 2015). Reports have found that astrocytes have a greater ability than neurons to take up glutamate, potentially because astrocytes can maintain a more stable membrane potential with high extracellular Na+ and low K+ compared to neurons, and neuronal firing makes neurons have a less stable Na+/K+ ratio (Mahmoud et al., 2019). Some electrophysiological studies have shown that the inward transport of 3 Na+ and 1 H+ ions with each glutamate anion drives the outward transport of 2 K+ ions, relying on their concentration gradients (Levy et al., 1998). Moreover, the transport of many other ions, such as Cl− and H+, may not directly drive glutamate uptake but may cause changes in the ionic concentrations within astrocytes (Untiet et al., 2017). Upon transportation into astrocytes, glutamate either follows the glutamine synthase pathway, wherein it converts into glutamine, or enters the TCA cycle where it converts to α-ketoglutarate, a substrate for ATP production (Waniewski and Martin, 1986). The preference between these two pathways is contingent on the extracellular concentration of glutamate (). If the concentration is less than 0.2 mM, glutamate is metabolized into glutamine for reuse, while oxidative metabolism is favored if the glutamate concentration surpasses 0.2 mM (McKenna et al., 1996). Glutamine, which is released into the extracellular space by astrocytes, is imported into glutamatergic and GABAergic neurons to synthesize glutamate and GABA, respectively. When acting as a precursor for GABA synthesis, glutamine is converted to GABA via phosphate-activated glutaminase (PAG; Schousboe et al., 2013). In addition, some studies have shown that astrocytic release of glutamate to the surrounding neurons helps to synchronize their firing and modulate their excitatory transmission (Harada et al., 2015). Subsequent studies found that the elevation of intracellular Ca2+ in astrocytes induced glutamate release from astrocytes (), further expanding our understanding of astrocyte functionality (Figure 3).
Figure 3
Astrocytes are also involved in the uptake and metabolism of GABA synaptically through high-affinity GABA transporters (GATs; Scimemi, 2014), and GAT3 is mainly expressed in astrocytes among the GATs (Melone et al., 2015). Through coupling to the cotransport of 1 Cl− and 3 Na+, GABA can be transported into astrocytes but shows no stimulation of astrocyte metabolism (). GABA is then oxidized in astrocytes through the transfer of nitrogen to other amino acids via GABA transaminase (GABA-T), forming succinic semialdehyde. Subsequently, succinic semialdehyde is converted into succinate via succinic semialdehyde dehydrogenase (SSADH) and enters the TCA cycle (). Brain GABA metabolism is essential, and reports suggest that malfunctions of GABA-T and SSADH can cause severe encephalopathies (Malaspina et al., 2016; Koenig et al., 2017), and GABA metabolism in astrocytes plays an important role in supporting the synthesis of glutamine (). In addition to being metabolized in astrocytes, GABA can also be synthesized and released from astrocytes. Studies on cultured astrocytes showed that astrocytes can synthesize GABA using glutamate decarboxylase (GAD67) or polyamine putrescine, and the results were also verified in vivo (Woo et al., 2018; Kwak et al., 2020). All studies have demonstrated that GABA concentrations are strongly modulated by astrocytes to maintain neurotransmitter balance (Kilb and Kirischuk, 2022).
Glutamine synthesis is very important for astrocyte energy metabolism, and the astrocytic glutamine supply is crucial for neuronal function in the brain. The inhibition of glutamine synthesis can lead to disturbances in both excitatory and inhibitory transmission (Ortinski et al., 2010; Tani et al., 2014). α-ketoglutarate in the TCA cycle is the precursor of glutamine, and impaired TCA cycle function and astrocyte glutamine transfer influence the supply of glutamine for glutamate and GABA synthesis, leading to functional disruption in the brain (Zhou Y. et al., 2019; ). This intricate interplay between glutamate, glutamine, and GABA underscores the critical role of astrocytes in modulating neuronal functionality (Figure 3).
5.2. Glutathione: an important intermediary in the maintenance of the intracellular redox balance
Glutathione (GSH) is a tripeptide that serves as a critical antioxidant in the brain and affects multiple cellular functions (Iskusnykh et al., 2022), especially in astrocytes (Pérez-Sala and Pajares, 2023). GSH consists of cysteine, glutamic acid, and glycine residues and is widely distributed throughout the CNS. The synthesis of GSH is consistent across different tissues (). Initially, glutamic acid and cysteine serve as substrates to generate glutamylcysteine (γGluCys) by γ-glutamylcysteine synthetase. GSH is then produced from glycine and γGluCys by glutathione synthetase (Segura-Aguilar et al., 2022). The GSH system contains exogenous GSH, GSH synthesis, and GSH recycling (Pérez-Sala and Pajares, 2023). The maintenance of the GSH system is critical for the regulation and utilization of reactive oxygen and nitrogen species (Pérez-Sala and Pajares, 2023). GSH may affect many important signaling pathways in the CNS, including neurotransmission, enzyme activation, metal transport in cells, cellular differentiation and proliferation, and apoptosis (). Impaired GSH synthesis leads to disrupted cell signaling and an increased risk of neurological diseases ().
5.3. Serine metabolism: cross-communicating metabolism between astrocytes and neurons
L-serine and D-serine, the amino acids akin to glutamine, play a fundamental role in neuron–glia communication (Wolosker, 2011). These two amino acids are essential for excitatory neurotransmission within the central nervous system (CNS; Hashimoto et al., 1992; Wolosker et al., 2008). L-serine is biosynthesized from the glycolytic intermediate 3-phosphoglycerate (Yamasaki et al., 2001). 3-Phosphoglycerate is oxidized by phosphoglycerate dehydrogenase (Phgdh) using NAD+ to form 3-phosphohydroxypyruvate, which is then converted to phosphoserine in a transamination reaction catalyzed by 3-phosphohydroxypyruvate aminotransferase (Psat). Phosphoserine is finally dephosphorylated by 3-phosphoserine phosphatase (Psph), generating L-serine. Both in vitro and in vivo experiments suggest that Phgdh mRNA is mainly expressed in astrocytes and minimally expressed in neurons (). These findings also strongly suggest that L-serine in the CNS is exclusively synthesized by astrocytes. After being synthesized from glucose in astrocytes, L-serine is shuttled to neurons to fuel the synthesis of D-serine, and the serine shuttle mechanism adds to other possible forms of metabolic interchange between astrocytes and neurons (Wolosker and Radzishevsky, 2013).
D-serine is synthesized from L-serine, and a constant supply of L-serine is critical for D-serine synthesis (Wolosker et al., 2017). L-serine is supplied by astrocytes and transported into neurons through the serine shuttle mechanism (Wolosker et al., 2016). Astrocytic L-serine is shuttled to neurons and is crucial for sustaining neuronal synthesis of D-serine. Once L-serine is inside the neurons, mainly in glutamatergic neurons, it is converted into D-serine through the action of the serine racemase (SR) enzyme (Neame et al., 2019). This D-serine is then released during membrane depolarization. Additionally, D-serine released by neurons can also be absorbed by astrocytes for storage and subsequent activity-dependent release. Notably, D-serine plays a crucial role in pyruvate generation (Wolosker, 2011). Additionally, a study found that neuronal release of D-serine modulates N-methyl-D-aspartate receptor (NMDAR) function, and some of the D-serine produced by neurons might be transported into astrocytes and metabolized via the peroxisomal D-amino acid oxidase (DAO) enzyme (Wolosker and Radzishevsky, 2013). Many studies have demonstrated the importance of endogenous D-serine in mediating NMDAR activation for contextual and working memory in rodents (; Kaplan et al., 2018). The serine shuttle mechanism provides an important relationship between astrocytes and NMDAR function. Taken together, the serine pathway underscores the important role of astrocytes in neuronal functionality.
5.4. Kynurenine metabolism: the link between kynurenine metabolism and astrocytes
The kynurenine pathway (KP), responsible for the breakdown of tryptophan into kynurenine and its subsequent conversion into quinolinic acid, picolinic acid, acetyl-CoA, and NAD, plays a critical role in the production of cellular energy through NAD formation. The KP occurs in astrocytes, neurons, macrophages, glia, and so on (Savitz, 2020). The pathway in which tryptophan degrades into kynurenine is known as the kynurenine pathway (KP) and is one of the major regulatory mechanisms of the immune response (Lim et al., 2017). Some inflammatory mediators, such as IFN-γ, TNF-α, lipopolysaccharide (LPS), and viral proteins, can activate indoleamine 2,3 dioxygenase (IDO-1), subsequently activating the KP. The diverse products of kynurenine contribute to a range of functions related to neuron protection. Among kynurenic acids, L-kynurenine (L-KYN) is produced and plays a key role in the neurotoxic and neuroprotective directions of the pathway (Joisten et al., 2021). 4-Hydroxyquinoline-2-carboxylic acid (KYNA), which is a neuroprotective kynurenic acid, is formed directly from L-KYN in astrocytes. The production of KNYA is directly related to increased activity of kynurenine aminotransferases (KATs; ). A study found that KAT1/2 is mainly expressed in human astrocytes, converting KYN to KYNA, suggesting that astrocytes are the primary site for KYNA production in the brain.
Kynurenine conversion to kynurenic acid, for instance, can have neuroprotective effects by inhibiting ionotropic glutamate receptors at high concentrations and mitigating the activity of glycine on the NMDA receptor (Kessler et al., 1989). Research has shown that even at low concentrations, kynurenic acid can significantly impact glutamate levels (). Moreover, kynurenic acid can modulate cyclic adenosine monophosphate (cAMP) production by enhancing orphan G-protein-coupled receptor activity, thus suppressing several inflammatory pathways (Wirthgen et al., 2017). However, excessive concentrations of kynurenic acid may induce NMDA receptor hypofunction in cortical GABA interneurons, causing disinhibition of glutamate projections (Savitz, 2020). In contrast, quinolinic acid can induce cytotoxicity in neurons by hindering astrocyte glutamate reuptake (Stone and Perkins, 1981). Additionally, it can generate reactive oxygen species, disrupt the BBB, destabilize the cell cytoskeleton, promote tau phosphorylation, and disrupt autophagy (Savitz, 2020). Astrocytes, as noted in earlier reports, express most of the enzymes in the kynurenine pathway, except kynurenine-OHase, and can both produce and degrade quinolinic acid (Guillemin et al., 1999). Moreover, astrocytes can trigger kynurenine pathway activation, leading to the production of L-kynurenine, which can then be used to produce kynurenic acid (Guillemin et al., 1999). These observations underscore the critical role of astrocytes in supporting neuronal survival. By managing these metabolic pathways, astrocytes may help prevent the onset of neurological disorders.
6. Astrocyte metabolic pathways in neurological disorders
Astrocytes play a central role in the brain’s metabolic homeostasis, regulating both energy and redox balances (Mulica et al., 2021). In the event of neurological injury, astrocytes can be activated in response to insult. Reactive astrogliosis is a common pathological feature in many neurological disorders and may play a role in neuropathological progression (Zhou B. et al., 2019). Dysfunction of astrocytes and regulatory pathways, including proteins, ion channels, and protein synthesis, may lead to the development of neurological diseases (Pekny et al., 2016; ). For instance, impairment of astrocyte glutamate uptake and metabolic functions can lead to neuronal excitotoxicity and neurodegeneration (Sun et al., 2021; Satarker et al., 2022). Neurological disorders such as depression, dementia, AD, and epilepsy all show impaired astrocytic metabolism (McDonald et al., 2018; Tournissac et al., 2021). Furthermore, certain neurological imbalances have been associated with reduced glial densities in different brain regions (O'Leary et al., 2021). Changes in glial distributions may cause a shift in the brain’s metabolism. Accumulating evidence suggests that there is a strong correlation between changes in the brain’s metabolism functionality and neurological disorders (Procaccini et al., 2016). Earlier research has revealed a strong connection between astrocyte functionality and neurological diseases. Alterations in astrocytic function, particularly metabolic function, may be a key reason for the worsening of neurological diseases (Figure 4).
Figure 4
6.1. Impairment of astrocyte metabolic function in depression
Major depressive disorder (MDD) is a neurological condition caused by chronic exposure to stress. Its characteristics include loss of motivation, impaired social interactions, communication, and pervasive sadness (Luo et al., 2021). Clinical patients with MDD were found to exhibit reduced blood flow and glucose metabolism in the brain (Videbech, 2000). Furthermore, MDD patients have also been found to have impaired TCA cycle functionality, which decreases energy production and may lead to exacerbation of depression-like symptoms (). In MDD, a decrease in the number of astrocytes may lead to an imbalance in neurotransmission, synaptic connectivity, and metabolism (O'Leary and Mechawar, 2021). In postmortem brain tissues of MDD patients, astrocytes were found to have hypertrophic cell bodies and processes in the white matter of the anterior cingular cortex (ACC; Torres-Platas et al., 2011). Experimental models of depression have demonstrated a reduction in the number and density of GFAP-positive astrocytes in the prefrontal cortex (PFC), locus coeruleus, hippocampus, and amygdala, alongside changes in their morphology and functionality (Zhang et al., 2008; ; Rubinow et al., 2016). The reduction in astrocyte density in MDD patients is more prominent than that in neurons (Rajkowska and Miguel-Hidalgo, 2007; Rajkowska and Stockmeier, 2013). In depression, astrocytes undergo morphological alterations characterized by astrocyte atrophy throughout the brain (Zhao et al., 2022). This morphological change may signify impaired functionality of astrocytes in MDD.
Astrocytes are regulators of metabolic energy in the brain. Changes to astrocytic functions in depression primarily revolve around the neuroimmune state, neuronal transmission, and synaptic plasticity. Astrocytes can become reactive when chronically exposed to stress, which can lead to impairment of their functionalities, including intracellular and extracellular ionic regulation, gap junction-based cellular communication, and neurotransmitter metabolism (Guo et al., 2022; Miguel-Hidalgo, 2022). Many studies have indicated that astrocytes play a critical role in regulating various inflammatory signal transductors, such as gp130, transforming growth factor β receptor, interferon-γ receptor, and estrogen receptor α (; Zheng et al., 2021). Astrocytic release of these inflammatory factors can contribute to the development of depressive-like behaviors by causing impaired glutamate uptake (Haroon et al., 2017; ). During depression, inflammation causes the upregulation and release of astrocytic cytokines, which can stimulate a cascade of inflammatory changes, including the activation of proteins such as mitogen-activated protein kinases (MAPK; Ji et al., 2002; Gorina et al., 2011). Activation of the MAPK pathway by inflammation or other stress factors can cause activation of MAPK phosphatase (MKP), which inhibits extracellular signal-regulated kinase (ERK) and elicits depressive-like behavior (Wang and Mao, 2019). Research has revealed that acute inhibition of the ERK pathway has inconsistent results in inducing depressive-like behavior, and chronic pharmacological inhibition of ERK through repeated infusion of the specific MAPK kinase (MEK) inhibitor U0126 into the hippocampus and mPFC has been shown to cause depressive-like behavior (; ; Tronson et al., 2008; Qi et al., 2009; Todorovic et al., 2009). Overactivation of ERK has been shown to have antidepressive effects and can alleviate depression (Tronson et al., 2008). Taken together, chronic inhibition of the ERK pathway may be a reason for the development of depression pathology. Depression is a chronic type of disease, and ERK has been shown to have an important link in the development of this pathology. Targeting ERK in astrocytes may elicit antidepressive effects. Astrocytes may also exert antidepressive effects through the release of neuron-protective factors (Li et al., 2021). This shows a fundamental change in astrocytes and their functional changes in neurological disorders.
Astrocytes are connected with neuronal synapses and can influence neuronal excitability through the removal of neurotransmitters such as glutamate, GABA, and purines from the synaptic cleft (Semyanov and Verkhratsky, 2021). In a rat model of depression, the astrocytic potassium channel (Kir4.1) drives neuronal bursts in the lateral habenula (LHb), which suggests that it may serve an important function in astrocyte-neuron communication in depression (; Yang et al., 2018). It has been suggested that due to the upregulation of Kir4.1, T-type voltage-sensitive Ca2+ channels (T-VSCCs) in neurons are activated and initiate NMDAR-dependent neuronal bursts, causing the LHb to trigger depression (Zhao et al., 2022). Although recent research has suggested that the LHb is an important circuit in depression and that constant activation may be a contributing factor to the pathology of depression, it does not take into consideration the altered activation of GABA and Glu neurons in different brain regions.
Another factor that may contribute to the role of astrocytes in depression is the decrease in overall ATP generation and release to neighboring cells. In early research, Cao et al. found that ATP concentrations were drastically lowered in chronic social defeat syndrome (CSDS) mouse models compared with control mice, particularly in the PFC and hippocampus regions of the brain (; Wang et al., 2021). More recently, Xiong and his team found that impaired epoxyeicosatrienoic acid (EET) signaling can impede ATP release from astrocytes in the mPFC, inducing depressive-like behavior (Xiong et al., 2019). The dynamics of ATP release from astrocytes are crucial in preventing depressive-like behavior. ATP released from astrocytes can be used to modulate a plethora of functions, including various brain activities. ATP is released by astrocytes through Ca2+ flux, which has been found to regulate axon excitability (Lezmy et al., 2021). ATP can also influence the release of glutamate from astrocytes, thereby causing changes in neuronal modulation (Jeremic et al., 2001). Research has also found that impairment of the glutamate metabolic pathway can also lead to increased depression-like behavior (Lee et al., 2013). Impairment of the glutamate metabolic pathway can negatively affect dopaminergic neurons by insufficiently inhibiting kynurenine, causing decreased dopamine release (Kulagina et al., 2001). Furthermore, the decrease in neurotransmitters, including glutamate and dopamine, may result in decreased pyramidal neuron firing (Vitrac et al., 2014).
In addition to dopamine, serotonin is also reduced primarily due to the decrease in cholesterol levels in the body due to decreased appetite and body weight (Sun et al., 2015). This is important because cholesterol and blood lipids can decompose to form a substrate triose phosphate that can then be converted into pyruvate and enter the TCA cycle (Gu et al., 2021). In recent research, impairment of mitochondrial functionality was found in humans with MDD, such as lowered respiration and ATP-related oxygen consumption (Kuffner et al., 2020). In MDD mice, high levels of reactive oxygen species (ROS) were found, which may be due to NADPH deficiency due to impaired PPP. Notably, a decrease in glutathione in the PPP may also result in the accumulation of ROS that trigger oxidative stress, causing inflammation and possibly contributing to the worsening of depression (Ozaslan et al., 2019). This demonstrates the importance of astrocyte metabolism in neuronal functionality and depression.
6.2. Astrocyte metabolism and AD
Astrocytes’ metabolic pathways provide energy to neurons for various functions through neuron modulation, such as memory, motor, and cognitive functions (Padmashri et al., 2015; Santello et al., 2019; Lines et al., 2020). AD is a neurogenerative disorder that is characterized by progressive cognitive decline, loss of memory, and dementia. There are many theorized causes of AD, one of the main causes being metabolic dysfunction (). Significant metabolic coupling is present between astrocytes and neurons, especially during synaptic activity (Magistretti, 2006). In the onset stages of the AD mouse model, there was progressive astrocytic atrophy with decreased GFAP staining in the cortex and hippocampus of the brain (Yeh et al., 2011; ). However, in postmortem tissue of AD patients, it was found that there was progressive astrocytic hypertrophy and upregulation of GFAP (Simpson et al., 2010). The change in astrocyte morphology and a switch from an atrophic phenotype to a hypertrophic phenotype may be associated with the accumulation of Aβ. It is well accepted that in late stages of AD, the functionality of astrogliosis mostly revolves around Aβ clearance (Guenette, 2003; Nicoll and Weller, 2003). Astrocytes also play an integral role in regulating vasoconstriction and vasodilatation (Iadecola and Nedergaard, 2007). Through these two functions, it may be possible for reactive astrocytes to contribute to damage to the neurovascular unit at the onset of AD.
One of the main factors contributing to AD is the genetic risk of apolipoprotein E (APOE), mainly expressed in astrocytes, which contributes to the accumulation of β-amyloid in the brain (Verghese et al., 2013; ). Additionally, genes such as clusterin and fermitin family member 2, also expressed in astrocytes, are also closely related to AD (Preman et al., 2021). This emphasizes the importance of astrocytes in AD and the importance of considering their role in the disease. Earlier research showed that inhibition of astrogliosis exacerbated Aβ accumulation and pathology in AD mice (Kraft et al., 2013). Reactive astrocytes in regions with plaque buildup showed impaired Ca2+ dynamics (Kuchibhotla et al., 2009; ). Astrocyte Ca2+ hyperactivity can promote the release of detrimental factors, alter neuronal-glial communication, and impair synaptic transmission (; Verkhratsky et al., 2017a). Recent hypotheses suggest that astrocytes could be involved in Aβ production, as they upregulate β-secretase 1 and amyloid precursor protein (APP) in AD brains (). However, there are currently no definitive data pointing to astrocytes as a major source of β-amyloid. Instead, astrocytes may mainly participate in β-amyloid clearance through various mechanisms, such as producing β-amyloid-degrading proteases, extracellular APOE, ApoJ/Clusterin, α1-antichymotrypsin (ACT) and α2-macroglobulin (α2-M; Ries and Sastre, 2016; Preman et al., 2021). Mutation and dysfunction of astrocytes in the expression or regulation of these proteins during AD may be a reason for the altered clearance processes of Aβ.
In AD, astrocytes may shift the excitation-inhibition balance through the secretion of GABA (Jo et al., 2014). Normally, astrocytes in the brain do not contribute to GABA production; however, in AD, GABA is synthesized through the astrocytic putrescine-monoamine oxidase B pathway (MAO-B; Jo et al., 2014). Hypothetically, astrocytic GABA release may be a defensive mechanism to protect neurons from further harm that may arise from excitotoxicity caused by AD (). Although GABA synthesis may initially support neuron survival, the increase in MAO-B expression for GABA synthesis may result in elevated production of hydrogen peroxide, which may worsen the condition ().
In AD patients, the expression of EAAT1 and EAAT2 in brain astrocytes was found to be reduced, which can lead to impaired neuronal functionality (Liang et al., 2002). Neurodegeneration was also found to involve this mechanism, in which astrocytes with impaired glutamate uptake possessed lower EAAT2 and GLAST expression (Hefendehl et al., 2016). Impairment of the glutamate metabolic system may be one of the reasons for continuous memory loss and confusion in AD patients. Another metabolic change is the decrease in the brain’s glucose uptake and glycolysis, which can be viewed as the early onset of AD (; Tomi et al., 2013). It was found that metabolism-related genes, such as those responsible for the regulation of the glycolytic pathway and TCA cycle, were significantly downregulated in both an AD mouse model and AD patients (). The activity of glucose 6-phosphate dehydrogenase was found to be significantly decreased, while lactate dehydrogenase increased in the frontal and temporal cortexes in AD patients (Yun and Hoyer, 2000). Moreover, patients who have suffered from frontotemporal dementia exhibited glucose hypometabolism in the cortical regions of the brain ().
The hypometabolism of glucose may also be attributed to insulin resistance (Kang et al., 2017). Insulin was found to regulate glucose uptake and metabolism in astrocytes, and insulin resistance may be a contributing factor for AD (). Overproduction of insulin can affect astrocytes and Aβ accumulation by saturating insulin-degrading enzyme (IDE), which was also found to degrade Aβ (Kang et al., 2017). Aβ accumulation is one of the hallmarks of AD and has been found to alter metabolic pathways in the brain (). It was found that Aβ aggregates and is internalized into astrocytes through scavenger receptors located on the plasma membrane, which alters glucose metabolism. The accumulation of Aβ in astrocytes is responsible for increased ROS production and decreased glutathione levels, leading to oxidative stress and neuronal vulnerability (). Aβ accumulation has been found to be a key player in activating microglia and downregulating CX3C motif chemokine receptor 1 (CX3CR1; Grubman et al., 2019; Muzio et al., 2021). This activation may trigger synaptic neurotoxicity and neurodegeneration (Hansen et al., 2018; ). Notably, inhibition of this pathway has been found to alleviate synapse loss and neurodegeneration in murine models of AD (Wu et al., 2019; ). Recent research has found a bidirectional interaction between the nervous system and immune system, signifying that systemic inflammation could cause selective neuronal activation (). A pathological aspect of AD is that a breakdown of the BBB occurs, causing the infiltration of toxicants and immune cells into the brain (Sweeney et al., 2018). The degradation of the BBB in AD pathology is one of the causes of neuroinflammation and results in the activation of downstream cascades associated with neural injury and neurodegeneration (Sweeney et al., 2018). Postmortem analysis of AD patient brains revealed an accumulation of metal ions such as iron (Fe) and zinc (Zn) due to dysregulation (Lovell et al., 1998). These metal ions are found to colocalize with Aβ aggregates, suggesting that Aβ may cause the accumulation of Fe and Zn, which in turn induces ferroptosis and AMPAR-mediated neurotoxicity (Weiss et al., 1993; ). In more recent studies, it has been suggested that elevated epoxide hydroxylases in the brain could contribute to neuroinflammation observed in AD (). These epoxide hydroxylases can bind to and inhibit anti-inflammatory arachidonic acid derivatives, thereby promoting inflammation (; Pathak and Sriram, 2023a). It is interesting to note that Aβ accumulation can alter glucose metabolism as well as hydrogen peroxide production and glutathione release in cultured astrocytes, showing that ROS are produced through astrocytic metabolic dysfunction. The toxic effect of Aβ on astrocytes is mainly expressed through mitochondrial depolarization and loss of Ca2+ homeostasis (). Astrocyte mitochondrial dysfunction can influence the homeostatic transport of Na+/K+-ATPase, thereby driving the accumulation of neurotransmitters such as glutamate and GABA (; Jackson et al., 2014). ATP deficiency may affect glutamate clearance and thereby promote excitotoxicity (Preman et al., 2021). Taken together, the alteration to astrocytic glucose metabolism due to Aβ accumulation and its effects on neighboring neurons points to metabolic alterations as being a key culprit in the development of AD.
6.3. Astrocyte metabolism and epilepsy
Astrocytic regulation of metabolic function is paramount in the role it plays in epilepsy. Epilepsy is caused by the imbalance of excitatory and inhibitory neurons in the brain, which may be a cause of metabolic dysfunction (Reddy and Saini, 2021; Qi et al., 2022). Astrocytes can participate in neurotransmission by regulating ion concentrations and neurotransmitters (Tritsch and Bergles, 2007). In epilepsy, astrocytes adopt a reactive morphology (Heinemann et al., 2000; ), become uncoupled (), and lose domain organization (Oberheim et al., 2008). These changes can have a variety of influences on functionality. These morphological changes may lead to dysfunctions in glutamate clearance (). Changes to astrocytic functionalities in epileptic conditions may exacerbate epileptic symptoms. During epilepsy, the increase in K+ flux may result from ion channel dysregulation. Research has found that in epilepsy, downregulation of Kir4.1 reduces astrocytes’ ability to take up glutamate and K+ from the extracellular environment, leading to increased seizures (; ; Haj-Yasein et al., 2011). Structural analysis of astrocytes showed spatial overlap of the K+ channel Kir4.1 and aquaporin-4 (AQP4; Nielsen et al., 1997; Higashi et al., 2001). This research suggests that K+ uptake through Kir channels may depend on osmotic flux. This can indirectly affect the uptake and clearance of glutamate by astrocytes. The accumulation of glutamate in the brain due to the lack of uptake and clearance by astrocytes may be a key factor in epileptogenesis.
In temporal lobe epilepsy (TLE) patients, increased interictal glutamate levels and increased seizure-induced glutamate transients were found in the hippocampus (). This may be due to the impaired uptake of glutamate in the brain. A decrease in glutamine synthase was also discovered in epilepsy patients, suggesting that even after glutamate enters astrocytes, the clearance of glutamate may still be limited (). Glutamate uptake into astrocytes can trigger astrocytic glycolysis (). During excessive synaptic activity, a decrease in glucose and a rise in lactate were found, signifying that lactate becomes the primary energy source for neurons during energy-intensive activities ().
In clinical settings, patients with TLE were found to also have increased glucose uptake and metabolism during seizures, whereas it is severely reduced during the interictal period (). In addition to lactate being a viable fuel source for driving hippocampal epilepsy, glycogen stored in astrocytes can be transported into neurons through the lactate shuttle and converted into lactate for fuel (). It was found that in a methionine sulfoximine (MSO)-induced epilepsy mouse model, glycogen was rapidly metabolized during seizures but returned to normal during the interictal phase (). In MSO-induced epilepsy, the activity of the glutamate reuptake pathway was found to decrease, resulting in increased neuronal excitability (). Decreased activity of glutamate reuptake can also lead to loss of inhibition by GABAergic neurons due to impaired GABA synthesis and release (Liang et al., 2006). Astrocytes are found to form coupled networks of cells for various functions (Wallraff et al., 2006). These networks allow for the exchange of ions, second messengers, metabolites, and amino acids from astrocytes to neurons. Glucose trafficking through coupled astrocytes is necessary for hyperactivity, while extracellular glucose deprivation causes loss of synaptic hyperactivity that can be rescued when astrocytes are filled with glucose or lactate, showing the importance of metabolism in epilepsy formation. Furthermore, astrocytes were found to be involved in regulating neuronal synchronization and the spread of ictal activity through Ca2+ channels in the gap junction (). In contrast to their involvement in Ca2+ channel modulation, astrocytes are also thought to possess antiepileptic functions because reduced astrocytic coupling was found to cause extracellular K+ and glutamate build-up, resulting in depolarization and seizure generation (Pannasch et al., 2011; ). Taken together, astrocytes possess both pro-epilepsy and anti-epilepsy properties. It has been shown to be a regulator of glutamate homeostasis, while the glucose metabolic pathway is crucial for the development of epilepsy.
In contrast to dysfunction of astrocyte metabolism in epilepsy, inflammation has also been a contributing factor for the development of epileptogenesis (Hayatdavoudi et al., 2022). In response to neuronal injury caused by excitotoxicity, astrocytes can generate and release cytokines such as IL-1β, IL-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, monocyte chemoattractant protein-1 (MCP-1), and chemokine C-motif ligand 2 (CCL2; ; Kwon and Koh, 2020). These signals were found to be highly expressed in both experimental and human epileptogenic brain tissues, indicating that these inflammatory signals may be tied to epilepsy pathology (; ). TNF-α secreted by microglia can induce astrocyte reactivity (). Additionally, TNF-α has been shown to regulate neuronal activity and induce epilepsy by increasing glutamate neurotransmitter release (Shim et al., 2018). In earlier research, IL-1β release and activation through interleukin-converting enzyme (ICE) and caspase-1 may contribute to acute seizures and drug-resistant chronic epilepsy in mice (Maroso et al., 2011). Pharmacological inhibition of IL-1B synthesis using VX-765 has been found to reduce epileptic activity (Maroso et al., 2011). Astrocyte and microglial release of these cytokines may be a main contributing factor to epileptogenesis. Targeting inflammatory cytokines may be another effective option in epilepsy treatment, particularly in patients who have developed refractory epilepsy.
7. Conclusion and outlook
Astrocytes are an integral element of neurobiology and have been rapidly revealing themselves as more than a mere supportive player in the complexity of the brain’s neural circuit. Their intricate roles extend far beyond the basics of metabolic regulation and hold the potential to unlock novel insights into the complex etiology and progression of various neurological disorders, including depression, Alzheimer’s disease, and epilepsy. This emerging perspective compels a comprehensive reconsideration of our understanding of astrocytes. In fact, their central role in neurological health and disease suggests that in-depth exploration of their function is not only important but necessary to develop effective treatments for these conditions. Projecting into the future of neuroscience, the trajectory of astrocytic research appears clear and promising. Deeper exploration into the nuanced interaction between astrocytes and neurons, their symbiotic metabolic relationship, and the potential to restore their function in pathological states can open new avenues for the treatment and prevention of diverse neurological disorders. In conditions such as depression and AD, emerging research suggests that dysfunctional energy metabolism in terms of glucose utilization in astrocytes may be a pivotal factor that warrants further research. Another aspect worth researching is the dual role of astrocytes in neurological disorders. Whether astrocyte activation is beneficial in AD is still unclear. Targeting astrocytic metabolism holds immense potential for the development of therapeutic interventions targeting metabolic abnormalities. Similarly, in epilepsy, the role of astrocytes in regulating ion balance by modulating ion channels and neuronal communication appears to be compromised, implying that therapeutic strategies aiming to rectify these disruptions could be beneficial in controlling epileptic seizures. Interestingly, astrocytes seem to be a double-edged sword in regard to their behavior in epilepsy, acting both as protective agents and instigators. Thus, future research needs to focus on comprehending this dual role and how we can potentially manipulate it for use in therapeutic treatments. As we continue to make technological strides in our exploration of astrocytes, the potential to elucidate their complex roles increases. Understanding their unique vulnerabilities and harnessing their innate potential could unveil novel treatments and significantly improve the prognosis for individuals afflicted with neurological disorders. To summarize, the future trajectory of astrocyte research is replete with promise and potential that warrants further research.
Funding
This review was supported by grants from the National Natural Science Foundation of China (81971265).
Publisher’s note
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Statements
Author contributions
Y-mZ and Y-bQ conceived the idea, wrote the original manuscript, drew the figures and revised the manuscript. Y-nG, W-gC, and TZ edited the initial draft and revised the manuscript. JL and YZ provided financial support and revised the manuscript. All authors contributed to the article and approved the submitted version.
Acknowledgments
Graphical abstracts and figures were constructed using BioRender (https://biorender.com).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supplementary material
The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnins.2023.1217451/full#supplementary-material
References
1
AbramovA. Y.CanevariL.DuchenM. R. (2004). Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J. Neurosci.24, 565–575. doi: 10.1523/JNEUROSCI.4042-03.2004
2
AgulhonC.SunM. Y.MurphyT.MyersT.LauderdaleK.FiaccoT. A. (2012). Calcium signaling and gliotransmission in normal vs. reactive astrocytes. Front Pharmacol3:139. doi: 10.3389/fphar.2012.00139
3
AlberiniC. M.CruzE.DescalziG.BessieresB.GaoV. (2018). Astrocyte glycogen and lactate: new insights into learning and memory mechanisms. Glia66, 1244–1262. doi: 10.1002/glia.23250
4
AlbrechtJ.SonnewaldU.WaagepetersenH. S.SchousboeA. (2007). Glutamine in the central nervous system: function and dysfunction. Front. Biosci.12, 332–343. doi: 10.2741/2067
5
AllamanI.GavilletM.BelangerM.LarocheT.ViertlD.LashuelH. A.et al. (2010). Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability. J. Neurosci.30, 3326–3338. doi: 10.1523/JNEUROSCI.5098-09.2010
6
AlmeidaA.MoncadaS.BolanosJ. P. (2004). Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat. Cell Biol.6, 45–51. doi: 10.1038/ncb1080
7
AndersenJ. V.JakobsenE. (2020). Extensive astrocyte metabolism of γ-aminobutyric acid (GABA) sustains glutamine synthesis in the mammalian cerebral cortex. Glia68, 2601–2612. doi: 10.1002/glia.23872
8
AndersenJ. V.JakobsenE.WestiE. W.LieM. E. K.VossC. M.AldanaB. I.et al. (2020). Extensive astrocyte metabolism of gamma-aminobutyric acid (GABA) sustains glutamine synthesis in the mammalian cerebral cortex. Glia68, 2601–2612. doi: 10.1002/glia.23872
9
AndersenJ. V.SchousboeA.VerkhratskyA. (2022). Astrocyte energy and neurotransmitter metabolism in Alzheimer's disease: integration of the glutamate/GABA-glutamine cycle. Prog. Neurobiol.217:102331. doi: 10.1016/j.pneurobio.2022.102331
10
AndersonC. M.SwansonR. A. (2000). Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia32, 1–14.
11
AoyamaK.NakakiT. (2013). Impaired glutathione synthesis in neurodegeneration. Int. J. Mol. Sci.14, 21021–21044. doi: 10.3390/ijms141021021
12
AronicaE.CrinoP. B. (2011). Inflammation in epilepsy: clinical observations. Epilepsia52, 26–32. doi: 10.1111/j.1528-1167.2011.03033.x
13
ArranzA. M.De StrooperB. (2019). The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications. Lancet Neurol.18, 406–414. doi: 10.1016/S1474-4422(18)30490-3
14
AtenS.KiyoshiC. M.ArzolaE. P.PattersonJ. A.TaylorA. T.DuY.et al. (2022). Ultrastructural view of astrocyte arborization, astrocyte-astrocyte and astrocyte-synapse contacts, intracellular vesicle-like structures, and mitochondrial network. Prog. Neurobiol.213:102264. doi: 10.1016/j.pneurobio.2022.102264
15
Augusto-OliveiraM.ArrifanoG. P.TakedaP. Y.Lopes-AraújoA.Santos-SacramentoL.AnthonyD. C.et al. (2020). Astroglia-specific contributions to the regulation of synapses, cognition and behaviour. Neurosci. Biobehav. Rev.118, 331–357. doi: 10.1016/j.neubiorev.2020.07.039
16
BaluD. T.LiY.TakagiS.PrestiK. T.RamikieT. S.RookJ. M.et al. (2016). An mGlu5-positive allosteric modulator rescues the neuroplasticity deficits in a genetic model of NMDA receptor hypofunction in schizophrenia. Neuropsychopharmacology41, 2052–2061. doi: 10.1038/npp.2016.2
17
BarrosL. F. (2013). Metabolic signaling by lactate in the brain. Trends Neurosci.36, 396–404. doi: 10.1016/j.tins.2013.04.002
18
BeauquisJ.PaviaP.PomilioC.VinuesaA.PodlutskayaN.GalvanV.et al. (2013). Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer's disease. Exp. Neurol.239, 28–37. doi: 10.1016/j.expneurol.2012.09.009
19
BednerP.DupperA.HuttmannK.MullerJ.HerdeM. K.DublinP.et al. (2015). Astrocyte uncoupling as a cause of human temporal lobe epilepsy. Brain138, 1208–1222. doi: 10.1093/brain/awv067
20
Bernard-HelaryK.LapoubleE.ArdourelM.HevorT.CloixJ. F. (2000). Correlation between brain glycogen and convulsive state in mice submitted to methionine sulfoximine. Life Sci.67, 1773–1781. doi: 10.1016/s0024-3205(00)00756-6
21
BinderD. K.SteinhauserC. (2021). Astrocytes and epilepsy. Neurochem. Res.46, 2687–2695. doi: 10.1007/s11064-021-03236-x
22
BittnerC. X.ValdebenitoR.RuminotI.LoaizaA.LarenasV.Sotelo-HitschfeldT.et al. (2011). Fast and reversible stimulation of astrocytic glycolysis by K+ and a delayed and persistent effect of glutamate. J. Neurosci.31, 4709–4713. doi: 10.1523/JNEUROSCI.5311-10.2011
23
BoisonD.SteinhauserC. (2018). Epilepsy and astrocyte energy metabolism. Glia66, 1235–1243. doi: 10.1002/glia.23247
24
BolanosJ. P.AlmeidaA. (2010). The pentose-phosphate pathway in neuronal survival against nitrosative stress. IUBMB Life62, 14–18. doi: 10.1002/iub.280
25
BolanosJ. P.HealesS. J.LandJ. M.ClarkJ. B. (1995). Effect of peroxynitrite on the mitochondrial respiratory chain: differential susceptibility of neurones and astrocytes in primary culture. J. Neurochem.64, 1965–1972. doi: 10.1046/j.1471-4159.1995.64051965.x
26
BonventoG.BolanosJ. P. (2021). Astrocyte-neuron metabolic cooperation shapes brain activity. Cell Metab.33, 1546–1564. doi: 10.1016/j.cmet.2021.07.006
27
BrandeburaA. N.PaumierA.OnurT. S.AllenN. J. (2023). Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders. Nat. Rev. Neurosci.24, 23–39. doi: 10.1038/s41583-022-00641-1
28
BreaD.Veiga-FernandesH. (2022). Inflammation in the gut is encoded by neurons in the brain. Nature602, 217–218. doi: 10.1038/d41586-021-03802-x
29
BrownA. M.Baltan TekkokS.RansomB. R. (2004). Energy transfer from astrocytes to axons: the role of CNS glycogen. Neurochem. Int.45, 529–536. doi: 10.1016/j.neuint.2003.11.005
30
BrownA. M.TekkokS. B.RansomB. R. (2003). Glycogen regulation and functional role in mouse white matter. J. Physiol.549, 501–512. doi: 10.1113/jphysiol.2003.042416
31
CaiH.CongW. N.JiS.RothmanS.MaudsleyS.MartinB. (2012). Metabolic dysfunction in Alzheimer's disease and related neurodegenerative disorders. Curr. Alzheimer Res.9, 5–17. doi: 10.2174/156720512799015064
32
CaoX.LiL. P.WangQ.WuQ.HuH. H.ZhangM.et al. (2013). Astrocyte-derived ATP modulates depressive-like behaviors. Nat. Med.19, 773–777. doi: 10.1038/nm.3162
33
CarpenedoR.PittalugaA.CozziA.AttucciS.GalliA.RaiteriM.et al. (2001). Presynaptic kynurenate-sensitive receptors inhibit glutamate release. Eur. J. Neurosci.13, 2141–2147. doi: 10.1046/j.0953-816x.2001.01592.x
34
CavusI.KasoffW. S.CassadayM. P.JacobR.GueorguievaR.SherwinR. S.et al. (2005). Extracellular metabolites in the cortex and hippocampus of epileptic patients. Ann. Neurol.57, 226–235. doi: 10.1002/ana.20380
35
ChaiH.Diaz-CastroB.ShigetomiE.MonteE.OcteauJ. C.YuX.et al. (2017). Neural circuit-specialized astrocytes: transcriptomic, proteomic, morphological, and functional evidence. Neuron95, 531–549.e539. doi: 10.1016/j.neuron.2017.06.029
36
ChattonJ. Y.PellerinL.MagistrettiP. J. (2003). GABA uptake into astrocytes is not associated with significant metabolic cost: implications for brain imaging of inhibitory transmission. Proc. Natl. Acad. Sci. U. S. A.100, 12456–12461. doi: 10.1073/pnas.2132096100
37
ChenY.TianZ.LiangZ.SunS.DaiC. L.LeeM. H.et al. (2012). Brain gene expression of a sporadic (icv-STZ mouse) and a familial mouse model (3xTg-AD mouse) of Alzheimer's disease. PLoS One7:e51432. doi: 10.1371/journal.pone.0051432
38
ChenJ. J.XieJ.LiW. W.BaiS. J.WangW.ZhengP.et al. (2019). Age-specific urinary metabolite signatures and functions in patients with major depressive disorder. Aging (Albany NY)11, 6626–6637. doi: 10.18632/aging.102133
39
ChenR.XueG.HölscherC. (2021). The role of the TNFα-mediated astrocyte signaling pathway in epilepsy. Acta Epileptologica3:24. doi: 10.1186/s42494-021-00059-9
40
ChengY.SongY.ChenH.LiQ.GaoY.LuG.et al. (2021). Ferroptosis mediated by lipid reactive oxygen species: a possible causal link of Neuroinflammation to neurological disorders. Oxidative Med. Cell. Longev.2021:5005136. doi: 10.1155/2021/5005136
41
CheungG.BataveljicD. (2022). Physiological synaptic activity and recognition memory require astroglial glutamine. Nat Commun13:753. doi: 10.1038/s41467-022-28331-7
42
CheverO.DjukicB.McCarthyK. D.AmzicaF. (2010). Implication of Kir4.1 channel in excess potassium clearance: an in vivo study on anesthetized glial-conditional Kir4.1 knock-out mice. J. Neurosci.30, 15769–15777. doi: 10.1523/JNEUROSCI.2078-10.2010
43
ChunH.ImH.KangY. J.KimY.ShinJ. H.WonW.et al. (2020). Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer's disease via H(2)O(2)(−) production. Nat. Neurosci.23, 1555–1566. doi: 10.1038/s41593-020-00735-y
44
CobbJ. A.O’NeillK.MilnerJ.MahajanG. J.LawrenceT. J.MayW. L.et al. (2016). Density of GFAP-immunoreactive astrocytes is decreased in left hippocampi in major depressive disorder. Neuroscience316, 209–220. doi: 10.1016/j.neuroscience.2015.12.044
45
ColomboJ. A. (2018). Interlaminar glia and other glial themes revisited: pending answers following three decades of glial research. Neuroglia1, 7–20. doi: 10.3390/neuroglia1010003
46
ColomboE.FarinaC. (2016). Astrocytes: key regulators of Neuroinflammation. Trends Immunol.37, 608–620. doi: 10.1016/j.it.2016.06.006
47
CottoB.NatarajaseenivasanK.LangfordD. (2019). Astrocyte activation and altered metabolism in normal aging, age-related CNS diseases, and HAND. J. Neurovirol.25, 722–733. doi: 10.1007/s13365-019-00721-6
48
CoulterD. A.EidT. (2012). Astrocytic regulation of glutamate homeostasis in epilepsy. Glia60, 1215–1226. doi: 10.1002/glia.22341
49
CruzN. F.DienelG. A. (2002). High glycogen levels in brains of rats with minimal environmental stimuli: implications for metabolic contributions of working astrocytes. J. Cereb. Blood Flow Metab.22, 1476–1489. doi: 10.1097/01.WCB.0000034362.37277.C0
50
CuiY.YangY.NiZ.DongY.CaiG.FoncelleA.et al. (2018). Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. Nature554, 323–327. doi: 10.1038/nature25752
51
CunnaneS. C.CrawfordM. A. (2014). Energetic and nutritional constraints on infant brain development: implications for brain expansion during human evolution. J. Hum. Evol.77, 88–98. doi: 10.1016/j.jhevol.2014.05.001
52
DeitmerJ. W.TheparambilS. M.RuminotI.NoorS. I.BeckerH. M. (2019). Energy dynamics in the brain: contributions of astrocytes to metabolism and pH homeostasis. Front. Neurosci.13:1301. doi: 10.3389/fnins.2019.01301
53
DejanovicB.WuT.TsaiM.-C.GraykowskiD.GandhamV. D.RoseC. M.et al. (2022). Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models. Nature Aging2, 837–850. doi: 10.1038/s43587-022-00281-1
54
DezsiL.TukaB.MartosD.VecseiL. (2015). Alzheimer's disease, astrocytes and kynurenines. Curr. Alzheimer Res.12, 462–480. doi: 10.2174/156720501205150526114000
55
DhillonK. K.GuptaS. (2022). “Biochemistry, ketogenesis” in Stat Pearls (Treasure Island, (FL): StatPearls Publishing).
56
Diaz-GarciaC. M.MongeonR.LahmannC.KovealD.ZuckerH.YellenG. (2017). Neuronal stimulation triggers neuronal glycolysis and not lactate uptake. Cell Metab.26, 361–374 e364. doi: 10.1016/j.cmet.2017.06.021
57
DienelG. A. (2019). Brain glucose metabolism: integration of energetics with function. Physiol. Rev.99, 949–1045. doi: 10.1152/physrev.00062.2017
58
DingF.YaoJ.RettbergJ. R.ChenS.BrintonR. D. (2013). Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: implication for bioenergetic intervention. PLoS One8:e79977. doi: 10.1371/journal.pone.0079977
59
DjukicB.CasperK. B.PhilpotB. D.ChinL. S.McCarthyK. D. (2007). Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J. Neurosci.27, 11354–11365. doi: 10.1523/JNEUROSCI.0723-07.2007
60
DongR.HanY.JiangL.LiuS.ZhangF.PengL.et al. (2022). Connexin 43 gap junction-mediated astrocytic network reconstruction attenuates isoflurane-induced cognitive dysfunction in mice. J. Neuroinflammation19:64. doi: 10.1186/s12974-022-02424-y
61
DringenR.BrandmannM.HohnholtM. C.BlumrichE. M. (2015). Glutathione-dependent detoxification processes in astrocytes. Neurochem. Res.40, 2570–2582. doi: 10.1007/s11064-014-1481-1
62
DumanC. H.SchlesingerL.KodamaM.RussellD. S.DumanR. S. (2007). A role for MAP kinase signaling in behavioral models of depression and antidepressant treatment. Biol. Psychiatry61, 661–670. doi: 10.1016/j.biopsych.2006.05.047
63
DzyubenkoE.HermannD. M. (2023). Role of glia and extracellular matrix in controlling neuroplasticity in the central nervous system. Semin Immunopathol45, 377–387. doi: 10.1007/s00281-023-00989-1
64
EdmondJ.HigaT. A.KorsakR. A.BergnerE. A.LeeW. N. (1998). Fatty acid transport and utilization for the developing brain. J. Neurochem.70, 1227–1234. doi: 10.1046/j.1471-4159.1998.70031227.x
65
EdmondJ.RobbinsR. A.BergstromJ. D.ColeR. A.de VellisJ. (1987). Capacity for substrate utilization in oxidative metabolism by neurons, astrocytes, and oligodendrocytes from developing brain in primary culture. J. Neurosci. Res.18, 551–561. doi: 10.1002/jnr.490180407
66
EidT.GhoshA.WangY.BeckstromH.ZaveriH. P.LeeT. S.et al. (2008). Recurrent seizures and brain pathology after inhibition of glutamine synthetase in the hippocampus in rats. Brain131, 2061–2070. doi: 10.1093/brain/awn133
67
EidT.LeeT. W.PatryloP.ZaveriH. P. (2019). Astrocytes and glutamine Synthetase in Epileptogenesis. J. Neurosci. Res.97, 1345–1362. doi: 10.1002/jnr.24267
68
EinatH.YuanP.GouldT. D.LiJ.DuJ.ZhangL.et al. (2003). The role of the extracellular signal-regulated kinase signaling pathway in mood modulation. J. Neurosci.23, 7311–7316. doi: 10.1523/JNEUROSCI.23-19-07311.2003
69
EngelJ.Jr.KuhlD. E.PhelpsM. E. (1983). Regional brain metabolism during seizures in humans. Adv. Neurol.34, 141–148.
70
EscartinC.GaleaE.LakatosA.O'CallaghanJ. P.PetzoldG. C.Serrano-PozoA.et al. (2021). Reactive astrocyte nomenclature, definitions, and future directions. Nat. Neurosci.24, 312–325. doi: 10.1038/s41593-020-00783-4
71
FalconeC.Wolf-OchoaM.AminaS.HongT.VakilzadehG.HopkinsW. D.et al. (2019). Cortical interlaminar astrocytes across the therian mammal radiation. J Comp Neurol527, 1654–1674. doi: 10.1002/cne.24605
72
FelgerJ. C. (2018). Imaging the role of inflammation in mood and anxiety-related disorders. Curr. Neuropharmacol.16, 533–558. doi: 10.2174/1570159X15666171123201142
73
FellinT.PascualO.GobboS.PozzanT.HaydonP. G.CarmignotoG. (2004). Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron43, 729–743. doi: 10.1016/j.neuron.2004.08.011
74
FernandezA. M.Hernandez-GarzonE.Perez-DomperP.Perez-AlvarezA.MederosS.MatsuiT.et al. (2017). Insulin regulates astrocytic glucose handling through cooperation with IGF-I. Diabetes66, 64–74. doi: 10.2337/db16-0861
75
FrostG. R.LiY. M. (2017). The role of astrocytes in amyloid production and Alzheimer's disease. Open Biol.7:228. doi: 10.1098/rsob.170228
76
FuW.JhamandasJ. H. (2014). Role of astrocytic glycolytic metabolism in Alzheimer's disease pathogenesis. Biogerontology15, 579–586. doi: 10.1007/s10522-014-9525-0
77
FuruyaS.TabataT.MitomaJ.YamadaK.YamasakiM.MakinoA.et al. (2000). L-serine and glycine serve as major astroglia-derived trophic factors for cerebellar Purkinje neurons. Proc. Natl. Acad. Sci. U. S. A.97, 11528–11533. doi: 10.1073/pnas.200364497
78
GarrettL. R.NiccoliT. (2022). Frontotemporal Dementia and Glucose Metabolism. Front. Neurosci.16:812222. doi: 10.3389/fnins.2022.812222
79
GendaE. N.JacksonJ. G.SheldonA. L.LockeS. F.GrecoT. M.O'DonnellJ. C.et al. (2011). Co-compartmentalization of the astroglial glutamate transporter, GLT-1, with glycolytic enzymes and mitochondria. J. Neurosci.31, 18275–18288. doi: 10.1523/JNEUROSCI.3305-11.2011
80
GhatakS.DolatabadiN.TrudlerD.ZhangX.WuY.MohataM.et al. (2019). Mechanisms of hyperexcitability in Alzheimer's disease hiPSC-derived neurons and cerebral organoids vs isogenic controls. elife8:e50333. doi: 10.7554/eLife.50333
81
GhoshA.ComerotaM. M.WanD.ChenF.PropsonN. E.HwangS. H.et al. (2020). An epoxide hydrolase inhibitor reduces neuroinflammation in a mouse model of Alzheimer's disease. Sci. Transl. Med.12:eabb1206. doi: 10.1126/scitranslmed.abb1206
82
GibbsM. E.AndersonD. G.HertzL. (2006). Inhibition of glycogenolysis in astrocytes interrupts memory consolidation in young chickens. Glia54, 214–222. doi: 10.1002/glia.20377
83
GiovannoniF.QuintanaF. J. (2020). The role of astrocytes in CNS inflammation. Trends Immunol.41, 805–819. doi: 10.1016/j.it.2020.07.007
84
Gomez-GonzaloM.LosiG.ChiavegatoA.ZontaM.CammarotaM.BrondiM.et al. (2010). An excitatory loop with astrocytes contributes to drive neurons to seizure threshold. PLoS Biol.8:e1000352. doi: 10.1371/journal.pbio.1000352
85
GorinaR.Font-NievesM.Marquez-KisinouskyL.SantaluciaT.PlanasA. M. (2011). Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways. Glia59, 242–255. doi: 10.1002/glia.21094
86
GrubmanA.ChewG.OuyangJ. F.SunG.ChooX. Y.McLeanC.et al. (2019). A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation. Nat. Neurosci.22, 2087–2097. doi: 10.1038/s41593-019-0539-4
87
GuX.KeS.WangQ.ZhuangT.XiaC.XuY.et al. (2021). Energy metabolism in major depressive disorder: recent advances from omics technologies and imaging. Biomed. Pharmacother.141:111869. doi: 10.1016/j.biopha.2021.111869
88
GuenetteS. Y. (2003). Astrocytes: a cellular player in Abeta clearance and degradation. Trends Mol. Med.9, 279–280. doi: 10.1016/s1471-4914(03)00112-6
89
GuilleminG. J.KerrS. J.SmytheG. A.ArmatiP. J.BrewB. J. (1999). Kynurenine pathway metabolism in human astrocytes. Adv. Exp. Med. Biol.467, 125–131. doi: 10.1007/978-1-4615-4709-9_18
90
GuoJ.QiuT.WangL.ShiL.AiM.XiaZ.et al. (2022). Microglia loss and astrocyte activation cause dynamic changes in hippocampal [(18)F]DPA-714 uptake in mouse models of depression. Front. Cell. Neurosci.16:802192. doi: 10.3389/fncel.2022.802192
91
GuzmanM.BlazquezC. (2001). Is there an astrocyte-neuron ketone body shuttle?Trends Endocrinol. Metab.12, 169–173. doi: 10.1016/s1043-2760(00)00370-2
92
GuzmanM.BlazquezC. (2004). Ketone body synthesis in the brain: possible neuroprotective effects. Prostaglandins Leukot. Essent. Fatty Acids70, 287–292. doi: 10.1016/j.plefa.2003.05.001
93
Haj-YaseinN. N.JensenV.VindedalG. F.GundersenG. A.KlunglandA.OttersenO. P.et al. (2011). Evidence that compromised K+ spatial buffering contributes to the epileptogenic effect of mutations in the human Kir4.1 gene (KCNJ10). Glia59, 1635–1642. doi: 10.1002/glia.21205
94
HansenD. V.HansonJ. E.ShengM. (2018). Microglia in Alzheimer's disease. J. Cell Biol.217, 459–472. doi: 10.1083/jcb.201709069
95
HaradaK.KamiyaT.TsuboiT. (2015). Gliotransmitter release from astrocytes: functional, developmental, and pathological implications in the brain. Front. Neurosci.9:499. doi: 10.3389/fnins.2015.00499
96
HaroonE.MillerA. H.SanacoraG. (2017). Inflammation, glutamate, and glia: a trio of trouble in mood disorders. Neuropsychopharmacology42, 193–215. doi: 10.1038/npp.2016.199
97
HashimotoA.NishikawaT.HayashiT.FujiiN.HaradaK.OkaT.et al. (1992). The presence of free D-serine in rat brain. FEBS Lett.296, 33–36. doi: 10.1016/0014-5793(92)80397-y
98
HayatdavoudiP.HosseiniM.HajaliV.HosseiniA.RajabianA. (2022). The role of astrocytes in epileptic disorders. Physiol. Rep.10:e15239. doi: 10.14814/phy2.15239
99
HefendehlJ. K.LeDueJ.KoR. W.MahlerJ.MurphyT. H.Mac VicarB. A. (2016). Mapping synaptic glutamate transporter dysfunction in vivo to regions surrounding Abeta plaques by iGluSnFR two-photon imaging. Nat. Commun.7:13441. doi: 10.1038/ncomms13441
100
HeinemannU.GabrielS.JauchR.SchulzeK.KiviA.EilersA.et al. (2000). Alterations of glial cell function in temporal lobe epilepsy. Epilepsia41, S185–S189. doi: 10.1111/j.1528-1157.2000.tb01579.x
101
Herrera Moro ChaoD.KirchnerM. K.PhamC.FoppenE.DenisR. G. P.CastelJ.et al. (2022). Hypothalamic astrocytes control systemic glucose metabolism and energy balance. Cell Metab.34, 1532–1547.e1536. doi: 10.1016/j.cmet.2022.09.002
102
HigashiK.FujitaA.InanobeA.TanemotoM.DoiK.KuboT.et al. (2001). An inwardly rectifying K(+) channel, Kir4.1, expressed in astrocytes surrounds synapses and blood vessels in brain. Am. J. Physiol. Cell Physiol.281, C922–C931. doi: 10.1152/ajpcell.2001.281.3.C922
103
HirabayashiY.FuruyaS. (2008). Roles of l-serine and sphingolipid synthesis in brain development and neuronal survival. Prog. Lipid Res.47, 188–203. doi: 10.1016/j.plipres.2008.01.003
104
IadecolaC.NedergaardM. (2007). Glial regulation of the cerebral microvasculature. Nat. Neurosci.10, 1369–1376. doi: 10.1038/nn2003
105
IskusnykhI. Y.ZakharovaA. A.PathakD. (2022). Glutathione in brain disorders and aging. Molecules27:324. doi: 10.3390/molecules27010324
106
JacksonR. J.MeltzerJ. C.NguyenH.ComminsC.BennettR. E.HudryE.et al. (2022). APOE4 derived from astrocytes leads to blood-brain barrier impairment. Brain145, 3582–3593. doi: 10.1093/brain/awab478
107
JacksonJ. G.O'DonnellJ. C.TakanoH.CoulterD. A.RobinsonM. B. (2014). Neuronal activity and glutamate uptake decrease mitochondrial mobility in astrocytes and position mitochondria near glutamate transporters. J. Neurosci.34, 1613–1624. doi: 10.1523/JNEUROSCI.3510-13.2014
108
JacksonJ. G.RobinsonM. B. (2018). Regulation of mitochondrial dynamics in astrocytes: mechanisms, consequences, and unknowns. Glia66, 1213–1234. doi: 10.1002/glia.23252
109
JensenN. J.WodschowH. Z.NilssonM.RungbyJ. (2020). Effects of ketone bodies on brain metabolism and function in neurodegenerative diseases. Int J Mol Sci21:8767. doi: 10.3390/ijms21228767
110
JeremicA.JeftinijaK.StevanovicJ.GlavaskiA.JeftinijaS. (2001). ATP stimulates calcium-dependent glutamate release from cultured astrocytes. J. Neurochem.77, 664–675. doi: 10.1046/j.1471-4159.2001.00272.x
111
JiR. R.SamadT. A.JinS. X.SchmollR.WoolfC. J. (2002). p38 MAPK activation by NGF in primary sensory neurons after inflammation increases TRPV1 levels and maintains heat hyperalgesia. Neuron36, 57–68. doi: 10.1016/s0896-6273(02)00908-x
112
JoS.YarishkinO.HwangY. J.ChunY. E.ParkM.WooD. H.et al. (2014). GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease. Nat. Med.20, 886–896. doi: 10.1038/nm.3639
113
JoistenN.RuasJ. L.BraidyN.GuilleminG. J.ZimmerP. (2021). The kynurenine pathway in chronic diseases: a compensatory mechanism or a driving force?Trends Mol. Med.27, 946–954. doi: 10.1016/j.molmed.2021.07.006
114
KamadaN.YasuharaA.IkedaM. (2003). Significance of the non-oxidative route of the pentose phosphate pathway for supplying carbon to the purine-nucleotide pathway in Corynebacterium ammoniagenes. J. Ind. Microbiol. Biotechnol.30, 129–132. doi: 10.1007/s10295-002-0014-0
115
KangS.LeeY. H.LeeJ. E. (2017). Metabolism-centric overview of the pathogenesis of Alzheimer's disease. Yonsei Med. J.58, 479–488. doi: 10.3349/ymj.2017.58.3.479
116
KaplanE.ZubedatS.RadzishevskyI.ValentaA. C.RechnitzO.SasonH.et al. (2018). ASCT1 (Slc1a4) transporter is a physiologic regulator of brain d-serine and neurodevelopment. Proc. Natl. Acad. Sci. U. S. A.115, 9628–9633. doi: 10.1073/pnas.1722677115
117
KasischkeK. A. (2009). “Activity-dependent metabolism in glia and neurons” in Encyclopedia of neuroscience. ed. SquireL. R. (Oxford: Academic Press), 53–60.
118
KesslerM.TerramaniT.LynchG.BaudryM. (1989). A glycine site associated with N-methyl-D-aspartic acid receptors: characterization and identification of a new class of antagonists. J. Neurochem.52, 1319–1328. doi: 10.1111/j.1471-4159.1989.tb01881.x
119
KilbW.KirischukS. (2022). GABA release from astrocytes in health and disease. Int. J. Mol. Sci.23:15859. doi: 10.3390/ijms232415859
120
KoenigM. K.HodgemanR.RivielloJ. J.ChungW.BainJ.ChiribogaC. A.et al. (2017). Phenotype of GABA-transaminase deficiency. Neurology88, 1919–1924. doi: 10.1212/wnl.0000000000003936
121
KoepsellH. (2020). Glucose transporters in brain in health and disease. Pflugers Arch.472, 1299–1343. doi: 10.1007/s00424-020-02441-x
122
KolA.AdamskyA.GroysmanM.KreiselT.LondonM.GoshenI. (2020). Astrocytes contribute to remote memory formation by modulating hippocampal-cortical communication during learning. Nat. Neurosci.23, 1229–1239. doi: 10.1038/s41593-020-0679-6
123
KoppelS. J.SwerdlowR. H. (2018). Neuroketotherapeutics: a modern review of a century-old therapy. Neurochem. Int.117, 114–125. doi: 10.1016/j.neuint.2017.05.019
124
KraftA. W.HuX.YoonH.YanP.XiaoQ.WangY.et al. (2013). Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J.27, 187–198. doi: 10.1096/fj.12-208660
125
KreftM.BakL. K.WaagepetersenH. S.SchousboeA. (2012). Aspects of astrocyte energy metabolism, amino acid neurotransmitter homoeostasis and metabolic compartmentation. ASN Neuro4:e00086. doi: 10.1042/an20120007
126
KuchibhotlaK. V.LattaruloC. R.HymanB. T.BacskaiB. J. (2009). Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science323, 1211–1215. doi: 10.1126/science.1169096
127
KuffnerK.TriebelhornJ.MeindlK.BennerC.ManookA.Sudria-LopezD.et al. (2020). Major depressive disorder is associated with impaired mitochondrial function in skin fibroblasts. Cells9:884. doi: 10.3390/cells9040884
128
KulaginaN. V.ZigmondM. J.MichaelA. C. (2001). Glutamate regulates the spontaneous and evoked release of dopamine in the rat striatum. Neuroscience102, 121–128. doi: 10.1016/s0306-4522(00)00480-2
129
KumariA. (2018). “Chapter 1- glycolysis” in Sweet Biochemistry. ed. KumariA. (London: Academic Press), 1–5.
130
KwakH.KohW.KimS.SongK.ShinJ. I.LeeJ. M.et al. (2020). Astrocytes control sensory acuity via tonic inhibition in the thalamus. Neuron108, 691–706.e610. doi: 10.1016/j.neuron.2020.08.013
131
KwonH. S.KohS. H. (2020). Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl Neurodegener9:42. doi: 10.1186/s40035-020-00221-2
132
Le FollC.LevinB. E. (2016). Fatty acid-induced astrocyte ketone production and the control of food intake. Am. J. Physiol. Regul. Integr. Comp. Physiol.310, R1186–R1192. doi: 10.1152/ajpregu.00113.2016
133
LeeY.MorrisonB. M.LiY.LengacherS.FarahM. H.HoffmanP. N.et al. (2012). Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature487, 443–448. doi: 10.1038/nature11314
134
LeeY.SonH.KimG.KimS.LeeD. H.RohG. S.et al. (2013). Glutamine deficiency in the prefrontal cortex increases depressive-like behaviours in male mice. J. Psychiatry Neurosci.38, 183–191. doi: 10.1503/jpn.120024
135
LeeH. G.WheelerM. A.QuintanaF. J. (2022). Function and therapeutic value of astrocytes in neurological diseases. Nat. Rev. Drug Discov.21, 339–358. doi: 10.1038/s41573-022-00390-x
136
LevyL. M.WarrO.AttwellD. (1998). Stoichiometry of the glial glutamate transporter GLT-1 expressed inducibly in a Chinese hamster ovary cell line selected for low endogenous Na+−dependent glutamate uptake. J. Neurosci.18, 9620–9628. doi: 10.1523/jneurosci.18-23-09620.1998
137
LezmyJ.Arancibia-CarcamoI. L.Quintela-LopezT.ShermanD. L.BrophyP. J.AttwellD. (2021). Astrocyte ca (2+)-evoked ATP release regulates myelinated axon excitability and conduction speed. Science374:eabh2858. doi: 10.1126/science.abh2858
138
LiY.LuoY.TangJ.LiangX.WangJ.XiaoQ.et al. (2021). The positive effects of running exercise on hippocampal astrocytes in a rat model of depression. Transl. Psychiatry11:83. doi: 10.1038/s41398-021-01216-x
139
LiangH.BourdonA. K. (2018). Gibbs free-energy gradient along the path of glucose transport through human glucose transporter 3. ACS Chem Neurosci9, 2815–2823. doi: 10.1021/acschemneuro.8b00223
140
LiangS. L.CarlsonG. C.CoulterD. A. (2006). Dynamic regulation of synaptic GABA release by the glutamate-glutamine cycle in hippocampal area CA1. J. Neurosci.26, 8537–8548. doi: 10.1523/JNEUROSCI.0329-06.2006
141
LiangZ.VallaJ.Sefidvash-HockleyS.RogersJ.LiR. (2002). Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer's disease patients. J. Neurochem.80, 807–814. doi: 10.1046/j.0022-3042.2002.00779.x
142
LimC. K.Fernández-GomezF. J.BraidyN.EstradaC.CostaC.CostaS.et al. (2017). Involvement of the kynurenine pathway in the pathogenesis of Parkinson's disease. Prog. Neurobiol.155, 76–95. doi: 10.1016/j.pneurobio.2015.12.009
143
LindbergD.HoA. M. C.PeytonL.ChoiD. S. (2019). Chronic ethanol exposure disrupts lactate and glucose homeostasis and induces dysfunction of the astrocyte-neuron lactate shuttle in the brain. Alcohol. Clin. Exp. Res.43, 1838–1847. doi: 10.1111/acer.14137
144
LinesJ.MartinE. D.KofujiP.AguilarJ.AraqueA. (2020). Astrocytes modulate sensory-evoked neuronal network activity. Nat. Commun.11:3689. doi: 10.1038/s41467-020-17536-3
145
LovellM. A.RobertsonJ. D.TeesdaleW. J.CampbellJ. L.MarkesberyW. R. (1998). Copper, iron and zinc in Alzheimer's disease senile plaques. J. Neurol. Sci.158, 47–52. doi: 10.1016/s0022-510x(98)00092-6
146
LuoH.JiangZ. L.RenY. (2021). Therapy Management of Metabolic Disorder Comorbidity with Depression. Front. Psychol.12:683320. doi: 10.3389/fpsyg.2021.683320
147
MaW.BergJ.YellenG. (2007). Ketogenic diet metabolites reduce firing in central neurons by opening K(ATP) channels. J. Neurosci.27, 3618–3625. doi: 10.1523/JNEUROSCI.0132-07.2007
148
MagistrettiP. J. (2006). Neuron-glia metabolic coupling and plasticity. J. Exp. Biol.209, 2304–2311. doi: 10.1242/jeb.02208
149
MagistrettiP. J.AllamanI. (2018). Lactate in the brain: from metabolic end-product to signalling molecule. Nat. Rev. Neurosci.19, 235–249. doi: 10.1038/nrn.2018.19
150
MahmoudS.GharagozlooM.SimardC.GrisD. (2019). Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release. Cells8:184. doi: 10.3390/cells8020184
151
MalaspinaP.RoulletJ. B.PearlP. L.AinslieG. R.VogelK. R.GibsonK. M. (2016). Succinic semialdehyde dehydrogenase deficiency (SSADHD): pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. Neurochem. Int.99, 72–84. doi: 10.1016/j.neuint.2016.06.009
152
MangiaS.SimpsonI. A.VannucciS. J.CarruthersA. (2009). The in vivo neuron-to-astrocyte lactate shuttle in human brain: evidence from modeling of measured lactate levels during visual stimulation. J. Neurochem.109 Suppl 1, 55–62. doi: 10.1111/j.1471-4159.2009.06003.x
153
MarosoM.BalossoS.RavizzaT.IoriV.WrightC. I.FrenchJ.et al. (2011). Interleukin-1beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics8, 304–315. doi: 10.1007/s13311-011-0039-z
154
McDonaldT.PuchowiczM.BorgesK. (2018). Impairments in oxidative glucose metabolism in epilepsy and metabolic treatments thereof. Front. Cell. Neurosci.12:274. doi: 10.3389/fncel.2018.00274
155
McKennaM. C.SonnewaldU.HuangX.StevensonJ.ZielkeH. R. (1996). Exogenous glutamate concentration regulates the metabolic fate of glutamate in astrocytes. J. Neurochem.66, 386–393. doi: 10.1046/j.1471-4159.1996.66010386.x
156
MeloneM.CiappelloniS.ContiF. (2015). A quantitative analysis of cellular and synaptic localization of GAT-1 and GAT-3 in rat neocortex. Brain Struct. Funct.220, 885–897. doi: 10.1007/s00429-013-0690-8
157
MergenthalerP.LindauerU.DienelG. A.MeiselA. (2013). Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci.36, 587–597. doi: 10.1016/j.tins.2013.07.001
158
Miguel-HidalgoJ. J. (2022). Astroglia in the vulnerability to and maintenance of stress-mediated neuropathology and depression. Front. Cell. Neurosci.16:869779. doi: 10.3389/fncel.2022.869779
159
MorlandC.LauritzenK. H.PuchadesM.Holm-HansenS.AnderssonK.GjeddeA.et al. (2015). The lactate receptor, G-protein-coupled receptor 81/hydroxycarboxylic acid receptor 1: expression and action in brain. J. Neurosci. Res.93, 1045–1055. doi: 10.1002/jnr.23593
160
MuJ.WangT.LiM.GuanT. (2022). Ketogenic diet protects myelin and axons in diffuse axonal injury. Nutr Neurosci25, 1534–1547. doi: 10.1080/1028415x.2021.1875300
161
MuddapuV. R.DharshiniS. A. P.ChakravarthyV. S.GromihaM. M. (2020). Neurodegenerative diseases-is metabolic deficiency the root cause?Front. Neurosci.14:213. doi: 10.3389/fnins.2020.00213
162
MulicaP.GrunewaldA.PereiraS. L. (2021). Astrocyte-neuron metabolic crosstalk in neurodegeneration: a mitochondrial perspective. Front Endocrinol (Lausanne)12:668517. doi: 10.3389/fendo.2021.668517
163
MuzioL.ViottiA.MartinoG. (2021). Microglia in Neuroinflammation and neurodegeneration: from understanding to therapy. Front. Neurosci.15:742065. doi: 10.3389/fnins.2021.742065
164
NadeauO. W.FontesJ. D.CarlsonG. M. (2018). The regulation of glycogenolysis in the brain. J. Biol. Chem.293, 7099–7107. doi: 10.1074/jbc.R117.803023
165
NeameS.SaforyH.RadzishevskyI.TouitouA.MarchesaniF.MarchettiM.et al. (2019). The NMDA receptor activation by d-serine and glycine is controlled by an astrocytic Phgdh-dependent serine shuttle. Biol Sci116, 20736–20742. doi: 10.1073/pnas.1909458116
166
NguyenY. T. K.HaH. T. T.NguyenT. H.NguyenL. N. (2021). The role of SLC transporters for brain health and disease. Cell Mol Life Sci79:20. doi: 10.1007/s00018-021-04074-4
167
NicollJ. A.WellerR. O. (2003). A new role for astrocytes: beta-amyloid homeostasis and degradation. Trends Mol. Med.9, 281–282. doi: 10.1016/s1471-4914(03)00109-6
168
NielsenS.NagelhusE. A.Amiry-MoghaddamM.BourqueC.AgreP.OttersenO. P. (1997). Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J. Neurosci.17, 171–180. doi: 10.1523/JNEUROSCI.17-01-00171.1997
169
OberheimN. A.TianG. F.HanX.PengW.TakanoT.RansomB.et al. (2008). Loss of astrocytic domain organization in the epileptic brain. J. Neurosci.28, 3264–3276. doi: 10.1523/JNEUROSCI.4980-07.2008
170
O'LearyL. A.BelliveauC.DavoliM. A.MaJ. C.TantiA.TureckiG.et al. (2021). Widespread decrease of cerebral vimentin-Immunoreactive astrocytes in depressed suicides. Front. Psych.12:640963. doi: 10.3389/fpsyt.2021.640963
171
O'LearyL. A.MechawarN. (2021). Implication of cerebral astrocytes in major depression: a review of fine neuroanatomical evidence in humans. Glia69, 2077–2099. doi: 10.1002/glia.23994
172
OrtinskiP. I.DongJ.MungenastA.YueC.TakanoH.WatsonD. J.et al. (2010). Selective induction of astrocytic gliosis generates deficits in neuronal inhibition. Nat. Neurosci.13, 584–591. doi: 10.1038/nn.2535
173
OzaslanM. S.BalciN.DemirY.GurbuzM.KufreviogluO. I. (2019). Inhibition effects of some antidepressant drugs on pentose phosphate pathway enzymes. Environ. Toxicol. Pharmacol.72:103244. doi: 10.1016/j.etap.2019.103244
174
PadmashriR.SureshA.BoskaM. D.DunaevskyA. (2015). Motor-skill learning is dependent on astrocytic activity. Neural Plast.2015:938023. doi: 10.1155/2015/938023
175
PannaschU.VargovaL.ReingruberJ.EzanP.HolcmanD.GiaumeC.et al. (2011). Astroglial networks scale synaptic activity and plasticity. Proc. Natl. Acad. Sci. U. S. A.108, 8467–8472. doi: 10.1073/pnas.1016650108
176
PanovA.OrynbayevaZ.VavilinV.LyakhovichV. (2014). Fatty acids in energy metabolism of the central nervous system. Biomed. Res. Int.2014:472459. doi: 10.1155/2014/472459
177
PataniR.HardinghamG. E.LiddelowS. A. (2023). Functional roles of reactive astrocytes in neuroinflammation and neurodegeneration. Nat Rev Neurol19, 395–409. doi: 10.1038/s41582-023-00822-1
178
PathakD.SriramK. (2023a). Molecular mechanisms underlying Neuroinflammation elicited by occupational injuries and toxicants. Int. J. Mol. Sci.24:2272. doi: 10.3390/ijms24032272
179
PathakD.SriramK. (2023b). Neuron-astrocyte omnidirectional signaling in neurological health and disease. Front. Mol. Neurosci.16:1169320. doi: 10.3389/fnmol.2023.1169320
180
PeknyM.PeknaM.MessingA.SteinhauserC.LeeJ. M.ParpuraV.et al. (2016). Astrocytes: a central element in neurological diseases. Acta Neuropathol.131, 323–345. doi: 10.1007/s00401-015-1513-1
181
PellerinL.MagistrettiP. J. (1994). Glutamate uptake into astrocytes stimulates aerobic glycolysis: a mechanism coupling neuronal activity to glucose utilization. Proc. Natl. Acad. Sci. U. S. A.91, 10625–10629. doi: 10.1073/pnas.91.22.10625
182
PellerinL.PellegriG.BittarP. G.CharnayY.BourasC.MartinJ. L.et al. (1998). Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev. Neurosci.20, 291–299. doi: 10.1159/000017324
183
Pérez-SalaD.PajaresM. A. (2023). Appraising the role of astrocytes as suppliers of neuronal glutathione precursors. Int J Mol Sci24:8059. doi: 10.3390/ijms24098059
184
PetrG. T.SunY.FrederickN. M. (2015). Conditional deletion of the glutamate transporter GLT-1 reveals that astrocytic GLT-1 protects against fatal epilepsy while neuronal GLT-1 contributes significantly to glutamate uptake into synaptosomes. J Neurosci35, 5187–5201. doi: 10.1523/jneurosci.4255-14.2015
185
PhatnaniH.ManiatisT. (2015). Astrocytes in neurodegenerative disease. Cold Spring Harb. Perspect. Biol.7:628. doi: 10.1101/cshperspect.a020628
186
PhelpsC. H. (1972). Barbiturate-induced glycogen accumulation in brain. An electron microscopic study. Brain Res39, 225–234. doi: 10.1016/0006-8993(72)90797-4
187
PierreK.MagistrettiP. J.PellerinL. (2002). MCT2 is a major neuronal monocarboxylate transporter in the adult mouse brain. J. Cereb. Blood Flow Metab.22, 586–595. doi: 10.1097/00004647-200205000-00010
188
Pralhada RaoR.VaidyanathanN.RengasamyM.Mammen OommenA.SomaiyaN.JagannathM. R. (2013). Sphingolipid metabolic pathway: an overview of major roles played in human diseases. J Lipids2013:178910. doi: 10.1155/2013/178910
189
PremanP.Alfonso-TrigueroM.AlberdiE.VerkhratskyA.ArranzA. M. (2021). Astrocytes in Alzheimer's disease: pathological significance and molecular pathways. Cells10:540. doi: 10.3390/cells10030540
190
ProcacciniC.SantopaoloM.FaicchiaD.ColamatteoA.FormisanoL.de CandiaP.et al. (2016). Role of metabolism in neurodegenerative disorders. Metabolism65, 1376–1390. doi: 10.1016/j.metabol.2016.05.018
191
QiY.ChengH.WangY.ChenZ. (2022). Revealing the precise role of Calretinin neurons in epilepsy: we are on the way. Neurosci. Bull.38, 209–222. doi: 10.1007/s12264-021-00753-1
192
QiX.LinW.WangD.PanY.WangW.SunM. (2009). A role for the extracellular signal-regulated kinase signal pathway in depressive-like behavior. Behav. Brain Res.199, 203–209. doi: 10.1016/j.bbr.2008.11.051
193
RajkowskaG.Miguel-HidalgoJ. J. (2007). Gliogenesis and glial pathology in depression. CNS Neurol. Disord. Drug Targets6, 219–233. doi: 10.2174/187152707780619326
194
RajkowskaG.StockmeierC. A. (2013). Astrocyte pathology in major depressive disorder: insights from human postmortem brain tissue. Curr. Drug Targets14, 1225–1236. doi: 10.2174/13894501113149990156
195
RasmussenR. N.SmithN. A. (2022). The elusive varicose astrocytes. Trends Neurosci.45, 94–95. doi: 10.1016/j.tins.2021.11.003
196
ReddyC.SainiA. G. (2021). Metabolic epilepsy. Indian J. Pediatr.88, 1025–1032. doi: 10.1007/s12098-020-03510-w
197
RiesM.SastreM. (2016). Mechanisms of Abeta clearance and degradation by glial cells. Front. Aging Neurosci.8:160. doi: 10.3389/fnagi.2016.00160
198
RobertsE. L.ChihC.-P. (2003). “A role for lactate released from astrocytes in energy production during neural activity?” in Advances in Molecular and Cell Biology Ed. HertzL. (University of Wisconsin, Madison, Wisconsin: Elsevier), 391–407.
199
RobertsE.FrankelS. (1950). Gamma-aminobutyric acid in brain: its formation from glutamic acid. J. Biol. Chem.187, 55–63.
200
RoseJ.BrianC.PappaA.PanayiotidisM. I.FrancoR. (2020). Mitochondrial metabolism in astrocytes regulates brain bioenergetics, neurotransmission and redox balance. Front Neurosci14:536682. doi: 10.3389/fnins.2020.536682
201
RubinowM. J.MahajanG.MayW.OverholserJ. C.JurjusG. J.DieterL.et al. (2016). Basolateral amygdala volume and cell numbers in major depressive disorder: a postmortem stereological study. Brain Struct. Funct.221, 171–184. doi: 10.1007/s00429-014-0900-z
202
San MartinA.Arce-MolinaR.GalazA.Perez-GuerraG.BarrosL. F. (2017). Nanomolar nitric oxide concentrations quickly and reversibly modulate astrocytic energy metabolism. J. Biol. Chem.292, 9432–9438. doi: 10.1074/jbc.M117.777243
203
Sánchez-AlvarezR.TaberneroA.MedinaJ. M. (2004). Endothelin-1 stimulates the translocation and upregulation of both glucose transporter and hexokinase in astrocytes: relationship with gap junctional communication. J. Neurochem.89, 703–714. doi: 10.1046/j.1471-4159.2004.02398.x
204
SantelloM.ToniN.VolterraA. (2019). Astrocyte function from information processing to cognition and cognitive impairment. Nat. Neurosci.22, 154–166. doi: 10.1038/s41593-018-0325-8
205
SartorettiM. M.CampetellaC. A. (2022). Dbx1 controls the development of astrocytes of the intermediate spinal cord by modulating notch signaling. Development149:dev200750. doi: 10.1242/dev.200750
206
SatarkerS.BojjaS. L.GurramP. C.MudgalJ.AroraD.NampoothiriM. (2022). Astrocytic glutamatergic transmission and its implications in neurodegenerative disorders. Cells11:1139. doi: 10.3390/cells11071139
207
SavitzJ. (2020). The kynurenine pathway: a finger in every pie. Mol. Psychiatry25, 131–147. doi: 10.1038/s41380-019-0414-4
208
SchousboeA.BakL. K.WaagepetersenH. S. (2013). Astrocytic control of biosynthesis and turnover of the neurotransmitters glutamate and GABA. Front Endocrinol (Lausanne)4:102. doi: 10.3389/fendo.2013.00102
209
ScimemiA. (2014). Structure, function, and plasticity of GABA transporters. Front. Cell. Neurosci.8:161. doi: 10.3389/fncel.2014.00161
210
Segura-AguilarJ.MuñozP.InzunzaJ.VarshneyM. (2022). Neuroprotection against aminochrome neurotoxicity: glutathione transferase M2-2 and DT-diaphorase. Antioxidants (Basel)11:296. doi: 10.3390/antiox11020296
211
SemyanovA.VerkhratskyA. (2021). Astrocytic processes: from tripartite synapses to the active milieu. Trends Neurosci.44, 781–792. doi: 10.1016/j.tins.2021.07.006
212
ShanL.ZhangT.FanK.CaiW.LiuH. (2021). Astrocyte-neuron signaling in synaptogenesis. Front. Cell Dev. Biol.9:680301. doi: 10.3389/fcell.2021.680301
213
SherwoodC. C.StimpsonC. D.RaghantiM. A.WildmanD. E.UddinM.GrossmanL. I.et al. (2006). Evolution of increased glia-neuron ratios in the human frontal cortex. Proc. Natl. Acad. Sci. U. S. A.103, 13606–13611. doi: 10.1073/pnas.0605843103
214
ShiL.TuB. P. (2015). Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr. Opin. Cell Biol.33, 125–131. doi: 10.1016/j.ceb.2015.02.003
215
ShimH. G.JangS. S.KimS. H.HwangE. M.MinJ. O.KimH. Y.et al. (2018). TNF-alpha increases the intrinsic excitability of cerebellar Purkinje cells through elevating glutamate release in Bergmann glia. Sci. Rep.8:11589. doi: 10.1038/s41598-018-29786-9
216
SimpsonJ. E.InceP. G.LaceG.ForsterG.ShawP. J.MatthewsF.et al. (2010). Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain. Neurobiol. Aging31, 578–590. doi: 10.1016/j.neurobiolaging.2008.05.015
217
SofroniewM. V. (2020). Astrocyte reactivity: subtypes, states, and functions in CNS innate immunity. Trends Immunol.41, 758–770. doi: 10.1016/j.it.2020.07.004
218
StoneT. W.PerkinsM. N. (1981). Quinolinic acid: a potent endogenous excitant at amino acid receptors in CNS. Eur. J. Pharmacol.72, 411–412. doi: 10.1016/0014-2999(81)90587-2
219
StorckT.SchulteS.HofmannK.StoffelW. (1992). Structure, expression, and functional analysis of a Na(+)-dependent glutamate/aspartate transporter from rat brain. Proc. Natl. Acad. Sci. U. S. A.89, 10955–10959. doi: 10.1073/pnas.89.22.10955
220
SunD.TanZ. B.SunX. D.LiuZ. P.ChenW. B.MilibariL.et al. (2021). Hippocampal astrocytic neogenin regulating glutamate uptake, a critical pathway for preventing epileptic response. Proc. Natl. Acad. Sci. U. S. A.118:e2022921118. doi: 10.1073/pnas.2022921118
221
SunS.YangS.MaoY.JiaX.ZhangZ. (2015). Reduced cholesterol is associated with the depressive-like behavior in rats through modulation of the brain 5-HT1A receptor. Lipids Health Dis.14:22. doi: 10.1186/s12944-015-0020-7
222
SweeneyM. D.SagareA. P.ZlokovicB. V. (2018). Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol.14, 133–150. doi: 10.1038/nrneurol.2017.188
223
TakahashiS. (2021). Neuroprotective function of high glycolytic activity in astrocytes: common roles in stroke and neurodegenerative diseases. Int. J. Mol. Sci.22:6568. doi: 10.3390/ijms22126568
224
TaniH.DullaC. G.FarzampourZ.Taylor-WeinerA.HuguenardJ. R.ReimerR. J. (2014). A local glutamate-glutamine cycle sustains synaptic excitatory transmitter release. Neuron81, 888–900. doi: 10.1016/j.neuron.2013.12.026
225
TodorovicC.SherrinT.PittsM.HippelC.RaynerM.SpiessJ. (2009). Suppression of the MEK/ERK signaling pathway reverses depression-like behaviors of CRF2-deficient mice. Neuropsychopharmacology34, 1416–1426. doi: 10.1038/npp.2008.178
226
TomiM.ZhaoY.ThamotharanS.ShinB. C.DevaskarS. U. (2013). Early life nutrient restriction impairs blood-brain metabolic profile and neurobehavior predisposing to Alzheimer's disease with aging. Brain Res.1495, 61–75. doi: 10.1016/j.brainres.2012.11.050
227
Torres-PlatasS. G.HercherC.DavoliM. A.MaussionG.LabonteB.TureckiG.et al. (2011). Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology36, 2650–2658. doi: 10.1038/npp.2011.154
228
TournissacM.LeclercM.Valentin-EscaleraJ.VandalM.BosoiC. R.PlanelE.et al. (2021). Metabolic determinants of Alzheimer's disease: a focus on thermoregulation. Ageing Res. Rev.72:101462. doi: 10.1016/j.arr.2021.101462
229
TritschN. X.BerglesD. E. (2007). Defining the role of astrocytes in neuromodulation. Neuron54, 497–500. doi: 10.1016/j.neuron.2007.05.008
230
TronsonN. C.SchrickC.FischerA.SananbenesiF.PagesG.PouyssegurJ.et al. (2008). Regulatory mechanisms of fear extinction and depression-like behavior. Neuropsychopharmacology33, 1570–1583. doi: 10.1038/sj.npp.1301550
231
UntietV.KovermannP.GerkauN. J.GenschT.RoseC. R.FahlkeC. (2017). Glutamate transporter-associated anion channels adjust intracellular chloride concentrations during glial maturation. Glia65, 388–400. doi: 10.1002/glia.23098
232
VergheseP. B.CastellanoJ. M.GaraiK.WangY.JiangH.ShahA.et al. (2013). ApoE influences amyloid-beta (Abeta) clearance despite minimal apoE/Abeta association in physiological conditions. Proc. Natl. Acad. Sci. U. S. A.110, E1807–E1816. doi: 10.1073/pnas.1220484110
233
VerkhratskyA.Rodriguez-ArellanoJ. J.ParpuraV.ZorecR. (2017a). Astroglial calcium signalling in Alzheimer's disease. Biochem. Biophys. Res. Commun.483, 1005–1012. doi: 10.1016/j.bbrc.2016.08.088
234
VerkhratskyA.ZorecR.ParpuraV. (2017b). Stratification of astrocytes in healthy and diseased brain. Brain Pathol.27, 629–644. doi: 10.1111/bpa.12537
235
VidebechP. (2000). PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr. Scand.101, 11–20. doi: 10.1034/j.1600-0447.2000.101001011.x
236
VitracC.PeronS.FrappeI.FernagutP. O.JaberM.GaillardA.et al. (2014). Dopamine control of pyramidal neuron activity in the primary motor cortex via D2 receptors. Front Neural Circuits8:13. doi: 10.3389/fncir.2014.00013
237
von BartheldC. S.BahneyJ.Herculano-HouzelS. (2016). The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J. Comp. Neurol.524, 3865–3895. doi: 10.1002/cne.24040
238
WallraffA.KohlingR.HeinemannU.TheisM.WilleckeK.SteinhauserC. (2006). The impact of astrocytic gap junctional coupling on potassium buffering in the hippocampus. J. Neurosci.26, 5438–5447. doi: 10.1523/JNEUROSCI.0037-06.2006
239
WamelinkM. M.StruysE. A.JakobsC. (2008). The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: a review. J. Inherit. Metab. Dis.31, 703–717. doi: 10.1007/s10545-008-1015-6
240
WangQ.KongY.WuD. Y.LiuJ. H.JieW.YouQ. L.et al. (2021). Impaired calcium signaling in astrocytes modulates autism spectrum disorder-like behaviors in mice. Nat. Commun.12:3321. doi: 10.1038/s41467-021-23843-0
241
WangJ. Q.MaoL. (2019). The ERK pathway: molecular mechanisms and treatment of depression. Mol. Neurobiol.56, 6197–6205. doi: 10.1007/s12035-019-1524-3
242
WaniewskiR. A.MartinD. L. (1986). Exogenous glutamate is metabolized to glutamine and exported by rat primary astrocyte cultures. J. Neurochem.47, 304–313. doi: 10.1111/j.1471-4159.1986.tb02863.x
243
WeissJ. H.HartleyD. M.KohJ. Y.ChoiD. W. (1993). AMPA receptor activation potentiates zinc neurotoxicity. Neuron10, 43–49. doi: 10.1016/0896-6273(93)90240-r
244
WenderR.BrownA. M.FernR.SwansonR. A.FarrellK.RansomB. R. (2000). Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J. Neurosci.20, 6804–6810.
245
WirthgenE.HoeflichA.ReblA.GuntherJ. (2017). Kynurenic acid: the Janus-faced role of an immunomodulatory tryptophan metabolite and its link to pathological conditions. Front. Immunol.8:1957. doi: 10.3389/fimmu.2017.01957
246
WoloskerH. (2011). Serine racemase and the serine shuttle between neurons and astrocytes. Biochim. Biophys. Acta1814, 1558–1566. doi: 10.1016/j.bbapap.2011.01.001
247
WoloskerH.BaluD. T.CoyleJ. T. (2016). The rise and fall of the d-serine-mediated Gliotransmission hypothesis. Trends Neurosci.39, 712–721. doi: 10.1016/j.tins.2016.09.007
248
WoloskerH.BaluD. T.CoyleJ. T. (2017). Astroglial versus neuronal D-serine: check your controls!Trends Neurosci.40, 520–522. doi: 10.1016/j.tins.2017.06.010
249
WoloskerH.DuminE.BalanL.FoltynV. N. (2008). D-amino acids in the brain: D-serine in neurotransmission and neurodegeneration. FEBS J.275, 3514–3526. doi: 10.1111/j.1742-4658.2008.06515.x
250
WoloskerH.RadzishevskyI. (2013). The serine shuttle between glia and neurons: implications for neurotransmission and neurodegeneration. Biochem. Soc. Trans.41, 1546–1550. doi: 10.1042/bst20130220
251
WooJ.MinJ. O.KangD. S.KimY. S.JungG. H.ParkH. J.et al. (2018). Control of motor coordination by astrocytic tonic GABA release through modulation of excitation/inhibition balance in cerebellum. Proc. Natl. Acad. Sci. U. S. A.115, 5004–5009. doi: 10.1073/pnas.1721187115
252
WuT.DejanovicB.GandhamV. D.GogineniA.EdmondsR.SchauerS.et al. (2019). Complement C3 is activated in human AD brain and is required for neurodegeneration in mouse models of amyloidosis and Tauopathy. Cell Rep.28, 2111–2123 e2116. doi: 10.1016/j.celrep.2019.07.060
253
WyssM. T.JolivetR.BuckA.MagistrettiP. J.WeberB. (2011). In vivo evidence for lactate as a neuronal energy source. J. Neurosci.31, 7477–7485. doi: 10.1523/JNEUROSCI.0415-11.2011
254
XiongW.CaoX.ZengY.QinX.ZhuM.RenJ.et al. (2019). Astrocytic Epoxyeicosatrienoic acid signaling in the medial prefrontal cortex modulates depressive-like behaviors. J. Neurosci.39, 4606–4623. doi: 10.1523/JNEUROSCI.3069-18.2019
255
XueX.LiuB.HuJ.BianX.LouS. (2022). The potential mechanisms of lactate in mediating exercise-enhanced cognitive function: a dual role as an energy supply substrate and a signaling molecule. Nutr. Metab. (Lond.)19:52. doi: 10.1186/s12986-022-00687-z
256
YamagataK. (2022). Lactate supply from astrocytes to neurons and its role in ischemic stroke-induced neurodegeneration. Neuroscience481, 219–231. doi: 10.1016/j.neuroscience.2021.11.035
257
YamasakiM.YamadaK.FuruyaS.MitomaJ.HirabayashiY.WatanabeM. (2001). 3-phosphoglycerate dehydrogenase, a key enzyme for l-serine biosynthesis, is preferentially expressed in the radial glia/astrocyte lineage and olfactory ensheathing glia in the mouse brain. J. Neurosci.21, 7691–7704. doi: 10.1523/jneurosci.21-19-07691.2001
258
YangY.CuiY.SangK.DongY.NiZ.MaS.et al. (2018). Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature554, 317–322. doi: 10.1038/nature25509
259
YaoZ. M.SunX. R.HuangJ.ChenL.DongS. Y. (2023). Astrocyte-neuronal communication and its role in stroke. Neurochem. Res. doi: 10.1007/s11064-023-03966-0. [Epub ahead of print].
260
YehC. Y.VadhwanaB.VerkhratskyA.RodriguezJ. J. (2011). Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer's disease. ASN Neuro3, 271–279. doi: 10.1042/AN20110025
261
YueQ.HoiM. P. M. (2023). Emerging roles of astrocytes in blood-brain barrier disruption upon amyloid-beta insults in Alzheimer's disease. Neural Regen. Res.18, 1890–1902. doi: 10.4103/1673-5374.367832
262
YunS. W.HoyerS. (2000). Effects of low-level lead on glycolytic enzymes and pyruvate dehydrogenase of rat brain in vitro: relevance to sporadic Alzheimer's disease?J. Neural Transm. (Vienna)107, 355–368. doi: 10.1007/s007020050030
263
ZeidanY. H.HannunY. A. (2007). Translational aspects of sphingolipid metabolism. Trends Mol. Med.13, 327–336. doi: 10.1016/j.molmed.2007.06.002
264
ZhangX.ZhangZ.XieC.XiG.ZhouH.ZhangY.et al. (2008). Effect of treatment on serum glial cell line-derived neurotrophic factor in depressed patients. Prog. Neuro-Psychopharmacol. Biol. Psychiatry32, 886–890. doi: 10.1016/j.pnpbp.2008.01.004
265
ZhaoY. F.RenW. J.ZhangY.HeJ. R.YinH. Y.LiaoY.et al. (2022). High, in contrast to low levels of acute stress induce depressive-like behavior by involving astrocytic, in addition to microglial P2X7 receptors in the rodent Hippocampus. Int. J. Mol. Sci.23:1904. doi: 10.3390/ijms23031904
266
ZhengZ. H.TuJ. L.LiX. H.HuaQ.LiuW. Z.LiuY.et al. (2021). Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala. Brain Behav. Immun.91, 505–518. doi: 10.1016/j.bbi.2020.11.007
267
ZhouY.DhaherR.ParentM.HuQ. X.HasselB.YeeS. P.et al. (2019). Selective deletion of glutamine synthetase in the mouse cerebral cortex induces glial dysfunction and vascular impairment that precede epilepsy and neurodegeneration. Neurochem. Int.123, 22–33. doi: 10.1016/j.neuint.2018.07.009
268
ZhouB.ZuoY. X.JiangR. T. (2019). Astrocyte morphology: diversity, plasticity, and role in neurological diseases. CNS Neurosci. Ther.25, 665–673. doi: 10.1111/cns.13123
Summary
Keywords
astrocyte, metabolism, neurological disorders, energy imbalance, neural circuit
Citation
Zhang Y, Qi Y, Gao Y, Chen W, Zhou T, Zang Y and Li J (2023) Astrocyte metabolism and signaling pathways in the CNS. Front. Neurosci. 17:1217451. doi: 10.3389/fnins.2023.1217451
Received
05 May 2023
Accepted
18 August 2023
Published
04 September 2023
Volume
17 - 2023
Edited by
Avital Schurr, University of Louisville, United States
Reviewed by
Ian A. Simpson, The Pennsylvania State University, United States; Dhruba Pathak, Centers for Disease Control and Prevention (CDC), United States
Updates
Copyright
© 2023 Zhang, Qi, Gao, Chen, Zhou, Zang and Li.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Jia Li, jli@simm.ac.cn; Yi Zang, yzang@simm.ac.cn
†These authors have contributed equally to this work
Disclaimer
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