Abstract
Serotonin is a key neurotransmitter that is implicated in a wide variety of behavioral and cognitive phenotypes. Originating in the raphe nuclei, 5-HT neurons project widely to innervate many brain regions implicated in the functions. During the development of the brain, as serotonin axons project and innervate brain regions, there is evidence that 5-HT plays key roles in wiring the developing brain, both by modulating 5-HT innervation and by influencing synaptic organization within corticolimbic structures. These actions are mediated by 14 different 5-HT receptors, with region- and cell-specific patterns of expression. More recently, the role of the 5-HT system in synaptic re-organization during adulthood has been suggested. The 5-HT neurons have the unusual capacity to regrow and reinnervate brain regions following insults such as brain injury, chronic stress, or altered development that result in disconnection of the 5-HT system and often cause depression, anxiety, and cognitive impairment. Chronic treatment with antidepressants that amplify 5-HT action, such as selective serotonin reuptake inhibitors (SSRIs), appears to accelerate the rewiring of the 5-HT system by mechanisms that may be critical to the behavioral and cognitive improvements induced in these models. In this review, we survey the possible 5-HT receptor mechanisms that could mediate 5-HT rewiring and assess the evidence that 5-HT-mediated brain rewiring is impacting recovery from mental illness. By amplifying 5-HT-induced rewiring processes using SSRIs and selective 5-HT agonists, more rapid and effective treatments for injury-induced mental illness or cognitive impairment may be achieved.
Introduction
Major Depressive Disorder (MDD) is characterized by a persistent low mood as a core symptom. The prevalence of depression is about 1 in 5 of the general population, affecting nearly 300 million people worldwide (1), and its prevalence has increased during the COVID-19 pandemic (2). The most recent global data place MDD as the third greatest source of disability, after low back pain and headache disorders (3). The currently available antidepressant drugs (ADs) have several disadvantages, including delayed efficacy (4–8 weeks) (4), numerous adverse effects that reduce tolerability (0.64- to 0.83-fold) and modest efficacy (1.15- to 1.55-fold) compared to placebo (5, 6) that limit therapeutic effectiveness to ~30% remission (7). Among approved ADs, selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment, and almost all target 5-HT and other monoamine systems (8). However, it is not fully understood why, despite brain levels of serotonin increasing with hours after SSRI administration, behavioral improvement takes weeks to be observed. This delay might reflect neuro-adaptive changes in pre-and post-synaptic cells, including long-term changes in gene expression, protein translation, or ultimately in neuroplasticity (9, 10). As it is diagnosed by a diversity of symptoms in the absence of biomarkers, major depression remains heterogeneous. A better understanding of the mechanism/s underlying the development of depression and its phenotypes will be critical to develop a more efficient, rational clinical approach to targeted treatment (10, 11).
Unraveling the pathophysiology of depression is a complex challenge. Not only are syndromes heterogeneous and the etiology diverse, but important symptoms such as guilt and suicidality cannot be reproduced in animal models. Nevertheless, other symptoms like anxiety, anhedonia, or behavioral despair have been modeled in animals (12–15), and these, together with clinical data, are providing insight into the neurobiology of mood disorders (16, 17) and antidepressant action (18). Recent studies combining behavioral, molecular, and functional imaging in transgenic mice have revealed that alterations in the functional connectivity of specific subpopulations of neurons forming a neural circuit result in depression-like behaviors (19–23). Understanding the underlying causes of these functional changes might offer a crucial new direction for the development of novel treatments for MDD in humans.
Serotonin Axon Hypothesis in Depression
In pre-clinical and clinical studies, deficits in serotonergic transmission including reductions in serotonin (5-hydroxytryptamine, 5-HT) neurons and their projections and increases in 5-HT autoinhibition have been associated with MDD and also with impaired responses to antidepressants (24–36). 5-HT is a monoamine neurotransmitter found mainly in blood platelets and the central nervous system (CNS) in animals and humans. It is widely implicated in mood, emotion, and happiness (37). The monoamine-serotonin hypothesis for depression was proposed in the 1960s suggesting that brain deficiency of monoamines, including 5-HT, triggers the onset of depression (38–40). It continues to guide research into the causes and treatments for depression, anxiety, and other mental illnesses.
The 5-HT System
The 5-HT neurons originating in the raphe midbrain innervate several regions of the brain (41–43). In 5-HT neurons, the enzyme tryptophan hydroxylase type 2 (TPH2) converts the amino acid tryptophan to 5-hydroxytryptophan (5-HTP) to catalyze the rate-limiting step in 5-HT biosynthesis (44–46). Subsequently, the L-aromatic amino acid decarboxylase (AADC) enzyme generates 5-HT. Alterations in 5-HT neurotransmission have been implicated in the pathophysiology of depression and its treatment. Based on clinical evidence that depressive symptoms improve following specific blockade of the 5-HT transporter (5-HTT) (47), early research focused on the uptake site at the terminal targets (48). The forebrain projecting raphe nuclei include the dorsal (DRN) and median (MRN) raphe and contain a diversity of 5-HT and non-5-HT neurons, identified using viral-genetic, immunohistochemistry and electrophysiology methods (49–51). For example, a small population of 5-HT immune-positive cells are not co-labeled with 5-HT1A receptors (52, 53) while some non-5-HT cells (such as GABA neurons) are co-labeled (52). Some 5-HT neurons co-express vesicular glutamate transporter-3 conferring glutamate neurotransmission and are implicated in anxiety behavior (54). Importantly, different projections of these neurons to target regions may confer stress susceptibility, depression or anxiety behaviors (36, 55, 56). Thus, the distinct properties of select 5-HT neuronal populations may confer behavioral phenotype and response to stress or injury.
In addition to developmental innervation, a unique capacity of the 5-HT system to regenerate or alter its innervation of brain regions has been observed after neurotoxin, traumatic or ischemic brain damage in rodents (57–64). Changes in 5-HT innervation have also been observed in non-lesion conditions such as repeated stress rodent models of depression (65, 66) and Parkinsonism in rodents (67) and primates (68). In post-mortem brain tissue from human depressed subjects, a reduction in 5-HT innervation has also been seen (32), although the functional role of these changes remains unclear.
The extensive ascending and descending 5-HT network projects throughout the brain and spinal cord making synaptic or non-synaptic contacts that release 5-HT (69–71). Actions of 5-HT are mediated by at least 14 different receptor subtypes (72). It is believed that 5-HT axons prenatally initiate axon outgrowth concomitant with the onset of 5-HT synthesis (73, 74). 5-HT axons form and grow in a targeted manner through guided pathfinding and arborization over several weeks. The 5-HT rich brain areas include cortical and sub-cortical regions. In addition, sensitive HPLC measurements of 5-HT and metabolites have shown that the metabolic activity of 5-HT fibers extending from DRN and MRN is parallels the tissue content of 5-HT (75). Therefore, it is expected that the alterations in 5-HT axons are associated with concomitant changes in 5-HT levels in the same brain region.
Development of 5-HT Projections
A large body of studies has characterized the molecular determinants involved in the developmental mechanisms targeting raphe 5-HT projections to the forebrain, proposing that alterations in these processes may predispose to mood disorders (74). Many of the transcription factors in the 5-HT gene regulatory network required for differentiation and maintenance of 5-HT neuronal subgroups have been extensively characterized, including Lmx1B, Pet-1/FEV, and others (76, 77). These factors may also be involved in axonal outgrowth as shown for Lmx1B (78); conditional deletion of Lmx1B in 5-HT neurons resulted in the loss of axonal projections to the forebrain and spinal cord in mice. Cytoskeleton-associated proteins growth-associated protein 43 (GAP-43) and a microtubule-associated protein, stable tubule only polypeptide (STOP) are also required for the growth and elongation of the 5-HT axons (76). In normal mice, GAP-43 is prenatally expressed on growing 5-HT axons; but in GAP-43 knockout mice, there is a loss of 5-HT immunoreactive innervation of the cortex and hippocampus (79). In the STOP knockout mice, 5-HT levels, as well as 5-HTT density and terminals, are reduced in projection areas such as hippocampus, but increased in the raphe suggesting impaired trafficking of 5-HT vesicles resulting in deficits in hippocampal neurogenesis, reduced anxiety, increased helplessness, and impaired cognitive function (80, 81). Despite these deficits in 5-HT innervation, no significant difference in the number of dorsal raphe 5-HT neurons was observed in GAP-43 or in STOP knockouts compared to wild-type littermates. These results suggest that GAP-43 and STOP proteins are the key regulators of normal 5-HT outgrowth and innervation in healthy conditions.
Concerning 5-HT axon pathfinding and guidance, Fenstermaker et al. (82) reported that Wnt signaling to planar cell polarity components is required for anterior to posterior axon projection and for proper orientation of 5-HT cell bodies in the raphe nuclei, using mice lacking individual planar cell polarity genes (82). In addition, to guide the 5-HT axons along the midline and form the long-distance connectivity both Robo1/2 and Slit1/2 have key roles in the formation of major forebrain tracts as shown in knockout mouse lines (83, 84).
Genes involved in cell adhesion have also been implicated in 5-HT axonal outgrowth in development, including the Pcdh-α isoforms (85, 86). In particular, loss of the αC2 isoform in serotonergic neurons, but not in 5-HT target brain regions, leads to abnormal projection and tiling of serotonergic axons, associated with increased depression-like behaviors (87). Interestingly, differentiation of induced pluripotent stem cells from SSRI-resistant compared to SSRI-responsive depressed patients to a serotonergic phenotype resulted in deficiencies in Pcdh-α expression and neurite outgrowth in vitro (88). More recently, an epigenome-wide association study of 150 monozygotic twins reported 428 differentially methylated genes associated with early-onset major depression, many of which are implicated in neurodevelopmental and cell adhesion genes including the protocadherin-α (Pcdh-α) gene cluster (89). Taken together these studies implicate Pcdh-α genes in 5-HT axonal outgrowth, major depression and response to SSRI antidepressants.
Visualizing Serotonin Axons
Early Markers
Early studies of 5-HT projections in the brain relied on a relatively insensitive formaldehyde-induced immunofluorescence method to visualize 5-HT (90). Subsequent studies used labeling with [3H]5-HT or immunostaining for 5-HT to visualize 5-HT axons in brain sections (71, 91). However, more recent studies have used the more sensitive approach of 5-HTT immunostaining to visualize 5-HT projections (92). In addition, antibodies to TPH have been useful, particularly in human post-mortem brain sections (41). These studies have revealed that 5-HT fibers rarely branch and have a high density in many brain regions. A high density of 5-HT projections has been shown in the cerebral cortex and subcortical regions including striatum, hippocampus, entorhinal cortex and the NAc [core and caudal shell (93)]. In a single fiber, there are several specialized boutons or varicosities where 5-HT is concentrated (91). It has been estimated that there are around 6 × 106 varicosities/mm3 in the rat cortex. In addition, each cortical neuron may receive around 200 varicosities (94, 95). However, there is evidence of some non-5-HT producing neurons that transiently express 5-HTT during development in the thalamus identified by 5-HT uptake and in situ hybridization for 5-HTT RNA (96). Using 5-HTT-cre mice to drive reporter gene expression, labeling was seen in dorsal thalamus, cingulate cortex, hippocampal CA3 neurons, retinal ganglion cells, superior olivary and cochlear nuclei during embryonic development and postnatally in medial prefrontal cortex (97). These studies suggest that neurons that lack TPH can take up 5-HT and in the thalamus can store the 5-HT in vesicles for co-transmission with glutamate. On the other hand, chronic SSRI-induced blockade of 5-HTT leads to uptake and release of 5-HT by the dopamine transporter in DA neurons (98, 99). Similar, l-DOPA treatment leads to DA uptake and release in 5-HT neurons (100), indicating cross-talk between monoamine systems at the level of co-transmission following chronic drug treatment.
Non-synaptic 5-HT/Volume Transmission
In addition to conventional synapses, serotonin is also released from varicosities into extracellular spaces with no target cell dendrites nearby (70, 101), a process termed volume transmission (102, 103). The non-synaptic release of 5-HT allows a paracrine transmission of serotonin to distal neurons and glia, particularly in the presence of 5-HT reuptake blockers, to activate high-affinity 5-HT receptors. Thus, both synaptic and non-synaptic 5-HT release may be implicated in the actions of raphe activation. As discussed below, activation by 5-HT of multiple 5-HT receptors engage several effector proteins to regulate neurite outgrowth, growth cone motility, synaptogenesis, and shape the dendritic spine and density in a wired brain.
The above examples illustrate that to identify 5-HT neurons and their projections it is important to combine different approaches. Recently, several genetic approaches using transgenic mice 5-HT-specific promoters (including 5-HTT, TPH2, Pet-1) to drive the expression of reporter genes (such as LacZ, YFP) have been used in combination with immunostaining for 5-HT markers (5-HT, 5-HTT, TPH2) to identify 5-HT projections (104, 105). These labeling approaches have been combined with anterograde and retrograde labeling techniques (106) to further define at a macroscopic level the neuroanatomy of the 5-HT system (56, 107–111). For example, at the cellular level, dual retrograde tracing revealed that a small (10–20%) proportion of neurons innervate both nucleus accumbens and medial prefrontal cortex (112). Single-cell biotin labeling has also been used to localize region-specific 5-HT/vGlut3 projections (113). These results indicate that single 5-HT neurons can innervate multiple brain regions.
Visualizing 5-HT Synapses
For high-resolution visualization of 5-HT synapses, electron microscopic (EM) studies (91) and 3D reconstruction of 5-HTT-positive axons have been used to map the 5-HT boutons located proximal to excitatory or inhibitory synapses in limbic brain regions (114, 115). Post-synaptic components of excitatory or inhibitory synapses form “triads”. To finely dissect how 5-HT exerts its modulatory actions, asymmetrical synapses/excitatory triads were mostly localized in the hippocampus, cortex, mPFC while symmetrical synapse/inhibitory triads were enriched in the dorsal raphe nucleus (DR), ventral tegmental area (VTA), central and basolateral amygdala (CeA, BLA) (116, 117). The combination of both (excitatory-inhibitory) was observed in areas like thalamic regions, bed nucleus of stria terminalis (BNST), and nucleus accumbens (NAc) (91, 114, 115). The preferential proximity of 5-HT boutons to neurochemical excitatory/inhibitory synapses could therefore suggest that serotonergic axons projecting to one area may preferentially target local glutamatergic, interneurons, or both to modulate their activity. For example, the preferential proximity of 5-HT-positive axon terminals to GABA terminals engaged in symmetrical synapses in DR and amygdala sub-regions (CeA, BLA) suggests that 5-HT mainly modulates the activity of interneurons in DR and amygdala. In contrast, 5-HT axon terminals are mainly engaged in asymmetrical synapses in mPFC to modulate the activity of excitatory neurons. Therefore, alterations in 5-HT system activity which preferentially change the activity of different cell types in target brain regions could differentially impact behavioral output. Recently, using a semi-automated approach that combines immunohistochemistry and high-resolution confocal microscopy to label 5-HTT immunoreactive axons has allowed researchers to reconstruct the 5-HT axons in 3D through their distribution within limbic brain regions (114, 115). Using this approach, the changes in 5-HT axon properties have been also determined in a model of post-stroke depression induced by focal ischemia in mice medial prefrontal cortex (mPFC), before and after treatment with chronic fluoxetine (64).
Imaging techniques have shown that the density and other features of 5-HT fibers can be altered during and after development. For example, Azmitia et al. (118) found that the density of serotonergic fibers is unusually high in the cerebral cortex of individuals suffering from autism spectrum disorders (118). In contrast, post-mortem studies in adult subjects showed that depression is associated with reduced 5-HT innervation of the orbitofrontal cortex in addition to the loss of hippocampal volume (32). Liu and Nakamura (65) reviewed the effects of chronic stress on regeneration of noradrenaline (NA) and 5-HT axons following NA or 5-HT neurotoxin in adult rats (65). They reported that, in contrast to NA axons, 5-HT axons are more dynamic in morphological plasticity as they are easily affected by stress and rapidly regenerate after damage. 5-HT axons also exert an inhibitory effect on NA axon regeneration. Furthermore, in a depression model induced by 9-week administration of interferon-α to adult male Sprague-Dawley rats, the density of 5-HT-stained axons decreased specifically in the ventral medial prefrontal cortex and amygdala (119). Thus, using new imaging approaches could promote the early diagnosis and development of more effective treatments for depression based on the morphological plasticity of 5-HT axons.
Volume Transmission: Beyond Synaptic Communication in the Wired Brain
Recent scientific evidence has focused on the complexities of neurotransmitter (NT) communication in the wired brain. In this regard, the importance and relevance of both fast-targeted synaptic and slow-non synaptic transmission has been recognized.
The concept of non-synaptic communication or volume transmission in the brain was proposed in the 1980s (102, 120), and shown for monoamines including 5-HT (117, 121). In 1994, Bjelke et al. showed indirect evidence that amphetamine-induced dopamine release may diffuse long distances following fiber tracts, possibly to the contralateral hemisphere (122). This is supported by the diffusion of Texas-Red-labeled dextran injection in the striatum, which diffuses along fiber tracts to the contralateral brain hemisphere (123). More recently, based on the half-life of dopamine it has been calculated that it might diffuse up to 7 microns (124). With newer, more sensitive indicators specific for dopamine and other monoamines (125), it may be possible to detect the diffusion of dopamine from non-synaptic release.
Using techniques such as receptor autoradiography, immunohistochemistry, and EM imaging has shown for monoamines a mismatch between the location of NTs relative to synaptic structures (103, 126, 127). For example, Martin et al. (128) showed that 94% of tyrosine hydroxylase-positive boutons in macaque prefrontal cortex Area 10 had no identifiable synaptic association in non-human primates (129). Rice et al. (130) modeled dopamine release to show that the presence of dopamine outside of the synaptic zone in the nigrostriatal pathway could be due to the spillover from the synaptic cleft and release into the surrounding extracellular space. Dopamine concentration remains sufficiently high to activate extra-synaptic dopamine receptors on surrounding cells (130). Mapping studies using diverse techniques also identified varicosities filled with NT granules localized along the axons. This evidence supports the existence of NTs in a high volume in non-terminal axon segments. Rodent studies showed that the main action of modulatory NTs including acetylcholine, norepinephrine, dopamine, and serotonin in the brain is through volume transmission via non-synaptic contacts of varicosities within axons (126).
After the first evidence supporting the concept of volume transmission in dopamine release in the brain by Fuxe and Ungerstedt (131), similar approaches were used for the 5-HT cell bodies located in dorsal raphe upon treatment of rats with 5-HT reuptake blocker clomipramine (132). The release of 5-HT from vesicles in the soma, dendrites, and/or axonal varicosities could also be independent of targeted synapses (133–135). More directly, parachloroamphetamine-induced non-synaptic somatodendritic release of 5-HT has been visualized using 3-photon microscopy of dorsal raphe sections (136). Somatodendritic and axonal release of 5-HT can be triggered by neuron depolarization, the stimulation of L-type calcium channels, activation of glutamatergic receptors, and/or by activation of 5-HT2 receptors (137). Furthermore, somatodendritic 5-HT release can also regulate the rate of discharge of serotonergic neurons and their tonic activity, via somatodendritic 5-HT1A and 5-HT2B autoreceptors (29, 138, 139). Nevertheless, direct evidence of 5-HT volume transmission-induced depression of 5-HT firing has not been reported (140). However, it has been recently shown that somatodendritic release of dopamine acting via D2 receptors autoinhibits the firing of the same neuron (141), suggesting a truly auto-regulatory system.
Axonal and Neurite Outgrowth: Serotonin Receptors
During development, differentiation of 5-HT neurons (e10.5–13 in rat) and outgrowth 5-HT projections is initiated early in embryonic development of the brain (e12–14 in rat) and continues well into post-natal development (p21 in rat) (73, 76, 142, 143). The availability of serotonin during embryonic to early post-natal developmental stages implicate serotonin signaling in directed axonal and neurite outgrowth during development (144, 145) and also in mediating neuroplasticity responses to external stimuli during and post-development (146). In this light, deletion of TPH2 to block neuronal 5-HT synthesis results in abnormal projections of 5-HT neurons both during development and in adults (147–150). Serotonin can also accumulate in (96, 151) and affect the development of non-serotonergic neurons in cortex and hippocampus (147, 152–155). Vicenzi and Gasperini (156) recently found that exogenous serotonin acts as a guidance cue during axon pathfinding in sensory neurons in vitro, capable of concentration-dependent attraction (via 5-HT2A receptor) or repulsion (via 5-HT1B receptor) of growth cone motility (156). However, the role of endogenously released 5-HT gradients in axonal outgrowth in vivo remains to be assessed.
The actions of serotonin on target cells, including glutamate and GABA neurons, are mediated by a large family of 5-HT receptors. Currently, genes for 14 receptors, including 13 distinct heptahelical G protein-coupled receptors (GPCRs) and one ligand-gated ion channel, have been identified. Based on their structural and downstream signaling characters, receptors are divided into seven distinct classes including 5-HT1-7 receptors (72, 157). The role of some key receptors in the 5-HT axonal transmission including axonal growth and axonal guidance is summarized below.
5-HT1 Receptors
The largest class of 5-HT receptors is the 5-HT1 receptor family characterized by an intronless coding sequence with five subtypes sharing 40–63% sequence homology (72, 157). The 5-HT1A,−1B,−1D,−1E and−1F receptors are localized in a wide variety of brain regions and show distinct pharmacological characteristics. The 5-HT1A receptors are broadly expressed in cortex, limbic areas, raphe nuclei (on 5-HT neurons as autoreceptors), in extrapyramidal areas, such as the substantia nigra, caudate-putamen, and in the cerebellum during embryonic-early postnatal development (158–168). The 5-HT1A receptors have been also found on astrocytes (169, 170) to mediate neuroprotective actions (171).
Using in vivo studies, Azmitia et al. (172) showed that 5-HT1A receptors have a key role in 5-HT-induced increases MAP2 and synaptophysin in the hippocampus, hypothalamus, parietal and temporal cortices, and the temporal pole (172). In vitro studies showed that 5-HT1A receptor stimulation decreased neurite outgrowth in cortical neurons (173), increased it in hippocampal cultures (174) while had no effect or inhibit outgrowth in serotonergic raphe neurons (175, 176). The 5-HT1A receptor can trigger diverse downstream signaling mechanisms that are region- and cell-specific and may mediate these actions (177, 178). 5-HT1A receptor coupling via Gβγ subunits reduces neuronal activity by opening potassium channels and closing calcium channels. However, the receptor is coupled primarily to Gi3 in 5-HT neurons and Gi2 in hippocampal neurons, which may underlie differential signaling and desensitization in these cells. While in 5-HT neurons, the 5-HT1A receptor appears to inhibit extracellular regulated protein kinase (ERK) ERK1/2 activity (179), it signals to activate it in developing and adult hippocampal neurons and may play roles in synaptogenesis (180). Recent studies implicate 5-HT1A signaling through Gβγ and tyrosine kinase receptors to activate ACII (181), phospholipase C (PLC)/protein kinase C (PKC) (182), calcium-calmodulin-dependent protein kinase II (CAMKII) (183), and phosphatidylinositol 3'-kinase (PI3K)/Akt signaling (184) mediating synaptogenesis, dendrite outgrowth, cell survival. Thus, the 5-HT1A receptor appears to modify its signaling repertoire depending on the cell type (5-HT vs. post-synaptic neurons) and the developmental state of the neuron (178). Previous studies also showed the crucial role of serotonin in modulating the neuronal guidance cues to shape the connectome in the wired brain mediated by the 5-HT1 family (185, 186). For example, 5-HT1B/1D receptor activation induces the growth and guidance of embryonic thalamocortical axons (187). In this process, axon responses to netrin-1 shift from attraction to repulsion during the cortical network shaping.
Cortical plasticity in adulthood can also be modified by 5-HT1 receptor activity. For example, chronic fluoxetine treatment induced a full recovery from monocular deprivation in adult rats by increasing brain-derived neurotrophic factor (BDNF) expression to reduce GABAergic activity in the visual cortex thus enhancing excitatory long-term potentiation (188). These actions of fluoxetine suggest that synaptic, possibly structural re-organization of the cortex can be induced in adulthood. Interestingly, these actions of fluoxetine were blocked by 5-HT1A antagonist WAY-100635, implicating 5-HT1A-induced BDNF expression in adult cortical plasticity (189). It remains unclear whether similar 5-HT1-induced signaling to BDNF in the PFC may mediate synaptic reorganization implicated in the antidepressant actions of SSRIs as seen for rapidly acting antidepressants such as ketamine (190, 191).
5-HT2 Receptors
The 5-HT2 receptor subtypes including 5-HT2A-C share about 50% amino acid sequence identity and show similarities concerning molecular structure, pharmacology, and signal transduction pathways (72, 192). 5-HT2A receptor expression is widely observed in cortical areas (neocortex, entorhinal, and piriform cortex), olfactory tubercle, dentate gyrus, and several brainstem nuclei, motor cranial nerve nuclei, and the spinal cord ventral horn (168, 193). In vitro studies have shown that stimulation of 5-HT2A receptors inhibits neurite growth in serotonergic neurons (176) while increasing neurite outgrowth in thalamic neurons (194), with no effects on cortical glutamatergic neurites (195). Recent studies by Vicenzi et al., (156) using a growth cone motility assay showed that serotonin is capable of acting as both attractive and repulsive guidance cue on its own axons via activation of 5-HT2A and 5-HT1B receptors, respectively (156). The low concentration of serotonin as 50 μM induces attraction mediated by 5-HT2A while twice this concentration elicits the repulsion through the stimulation of 5-HT1B. In agreement, high-resolution imaging of growth cones indicateds that differential signaling is involved. For these actions, 5-HT2A receptors signaled through their canonical pathways of endoplasmic reticulum-mediated calcium release and 5-HT1B through cAMP depletion.
5-HT3 Receptors
The 5-HT3 receptors, the only ligand-gated, non-selective cation channel 5-HT receptors, are expressed in the cerebral cortex, hippocampus, amygdala, and the solitary tract nucleus (196). The 5-HT3 receptor is not coupled to second-messenger cascades which makes it different from the other members of the 5-HT receptor family. The expression of 5-HT3 receptors in neuroblasts during brain development has suggested that they may play a role in neuronal differentiation and development (197). However, there is debate regarding the role of 5-HT3 receptors in neurite outgrowth, as 5-HT3 receptors may enhance dendritic spine formation in thalamic cultures (194), but not neurite outgrowth (198). For example, 5-HT3 receptors form a complex with the light chain of microtubule-associated protein 1B (MAP1B) and the tubulin cytoskeleton in dendrites and growth cones of hippocampal neurons during developmental (199). However, knockout of 5-HT3 receptor did not alter dendritic spines at baseline or following long-term depression in adult mice (200).
5-HT4 Receptors
5-HT4 receptors are implicated in the regulation of multiple physiological processes and are highly expressed in various regions of the limbic and in several basal ganglia components of the rodent brain (201–203). In transfected cell lines and primary neurons, 5-HT4 receptors primarily induce the cAMP pathway via Gs proteins (204), but can also signal to ERK activation via SRC protein kinase (205). In vitro studies showed that 5-HT4 receptor activation induces decreases in neurite outgrowth (206). By contrast, studies in the hippocampus also showed that 5-HT4 receptor activation enhances learning-induced hippocampal dendritic spine formation in vivo (207). 5-HT4 receptor activation was shown to rapidly trigger dendritic spine formation in hippocampal neurons (208) via G13-RhoA signaling pathway (209). Pharmacological studies showed that agonist-induced 5-HT4 receptor activation inhibits basal synaptic transmission and theta-burst LTP via GABAergic activation (210), while enhancing low-frequency induced hippocampal LTD (211). In contrast, 5-HT4 antagonist induced thalamostriatal spike timing-dependent LTD expression (212), while blocking 5-HT-induced late LTP in the amygdala (213). Therefore, the 5-HT4 receptor has a role in modulating synaptic transmission via the regulation of long-term plasticity. In addition, 5-HT4 receptors mediate SSRI-induced “dematuration” of adult hippocampal granule neurons implicated in behavioral actions (214, 215). Furthermore, the antidepressant actions of SSRI in depression models requires 5-HT4 receptors (216, 217). Interestingly 5-HT4 receptors have been implicated in rapid induction of hippocampal neurogenesis and rapid antidepressant actions (218). Since the above studies have used systemic 5-HT4 ligands, global 5-HT4 knockout mice, or slice preparations, the relative roles of 5-HT4 induced actions on region-specific synaptic transmission, neuroplasticity, and neurogenesis in its behavioral and cognitive actions remains to be clarified using tissue-specific gene knockout or drug delivery approaches.
5-HT6 Receptors
The 5-HT6 receptors are expressed in diverse brain areas including the olfactory tubercle, cortex, dorsal and ventral striatum, hippocampus, amygdala as well as choroid plexus (219–221), and are implicated in schizophrenia, anxiety, and Alzheimer's disease (222). The 5-HT6 receptor activates ACs by coupling to Gs proteins (223), interacts with Fyn kinase to mediate ras-MEK-ERK1/2 signaling (224, 225), and with Jab1 to couple to the transcription factor c-Jun (226). In vivo studies in the developing cortex have implicated 5-HT6 receptors localized in dendritic cilia in dendritic outgrowth and neuronal differentiation, signaling via the Fyn pathway (227, 228). Actions of 5-HT6 signaling on neurite outgrowth involve constitutive activation of the receptor by cdk5, which can be blocked by 5-HT6 antagonist (229, 230). In addition, 5-HT6 signaling regulates migration of cortical pyramidal neurons and interneurons during development (231, 232). More recently, 5-HT6-/- mice have been shown to have altered in vivo dendritic and neuronal morphology, increased neuronal excitability, and increased anxiety and cognitive impairment phenotypes (233). In terms of neurotransmission, agonist-induced 5-HT6 receptor activation acutely increases expression of BDNF and Arc in cortical and hippocampal brain areas (234) and in the hippocampal CA1 area increases GABA release and decreases synaptic plasticity (235, 236). Using a 5-HT6 receptor antagonist increases the levels of glutamate, acetylcholine, and catecholamine in the frontal cortex and hippocampus and results in enhanced excitatory neurotransmission. 5-HT6 receptor antagonists inhibit the mTOR complex, which promotes neuronal survival and increases neurite outgrowth (237). This 5-HT6 modulation of the mTOR complex provides a promising target to treat anxiety, schizophrenia, and Alzheimer's disease (230). Although an increasing body of studies indicates that acute effects of both 5-HT6 receptor antagonists and agonists elicit improvement in depression and anxiety observed in the preclinical models (238), the underlying mechanisms are not clear. Given the importance of 5-HT6 receptors in cortical development, this receptor may also play a role in the recovery and regeneration of 5-HT projections lost in adulthood and associated with cognitive impairment (239) and depression (238).
5-HT7 Receptors
The 5-HT7 receptors are involved in the sleep-wake cycle, body temperature, depression-like behavior and the processes of learning and memory (240–242). In the brain, they are mainly expressed in the thalamus, hypothalamus, hippocampus, prefrontal cortex, amygdala, lateral habenula, raphe nuclei, and the suprachiasmatic nucleus (240, 243, 244). 5-HT7 receptors couple to Gαs (245) and Gα12 (206). Gα12/13 proteins signal to activate JNK, G protein signaling proteins (RGS) (246), non-receptor tyrosine kinases (nRTK) to signal to the Rho family of small GTPases that promote neurite extension and branching (247, 248). In vitro studies reported the involvement of 5-HT7 receptors in neurite outgrowth, spino- and synaptogenesis in young neurons, and increases in axon outgrowth via mTOR, Cdc4, to regulate actin filaments dynamics and metalloproteinase induced synaptic remodeling (249–252). Interestingly, in postnatal development, the 5-HT7 receptor is co-expressed with 5-HTT on PFC neurons and mediates PFC projections to the DRN implicated in development of anxiety and depression like phenotypes in mice treated postnatally with SSRI (253). The role of 5-HT7 receptors in modifying PFC projections during adulthood remains to be elucidated.
Triggering 5-HT Axonal and Neurite Outgrowth
How is spontaneous 5-HT axonal outgrowth triggered? By analogy with activity-dependent neuroplasticity following stroke (254, 255), it is hypothesized that regrowth of 5-HT axons after an injury is driven by the activity of the affected 5-HT neurons. For example, following a stroke to the left mPFC, we have observed a 3–4 fold chronic activation (FosB+ cells) of dorsal raphe 5-HT and vGlut3-positive neurons that is maintained after fluoxetine treatment (256). Since full recovery of 5-HT innervation and behavior is only seen after chronic fluoxetine treatment (64), this suggests that fluoxetine-induced augmentation of 5-HT levels at target regions is critical for 5-HT innervation to mediate behavioral and cognitive recovery. This implicates 5-HT autoregulatory effects on its own axons in affected area, which may be mediated via 5-HT receptor signaling (as discussed above). The importance of 5-HT neuronal activation is suggested by deep brain stimulation of the mPFC in rats subjected to chronic social defeat. Increasing cortical drive to the raphe induced dendritic remodeling of 5-HT neurons to restore their activity, resulting in increased size and number of presynaptic 5-HT terminals in the hippocampus (66). The released 5-HT likely signals through a variety of 5-HT receptors on 5-HT projections, local glial cells and target neurons to ultimately restore behavior as discussed above.
Detecting 5-HT Axonal and Neurite Outgrowth in Humans
Does the loss of 5-HT innervation occur in clinical depression, and can it be reversed by chronic SSRI treatment? The problem is how to visualize 5-HT innervation in depressed patients. One method is to use the 5-HTT as a biomarker for 5-HT innervation. In post-mortem brain, several regions show reduced 5-HTT staining including the ventral PFC, which was associated with depression and childhood maltreatment (257, 258). More specifically, visualization and quantification of 5-HTT-immunopositive processes have shown a reduction in the length of 5-HT axons in orbitofrontal cortex from depressed subjects (32). This region integrates multi-model sensory input to drive reward and affective behavior (259), and its activity is inversely correlated with the severity of depression (260). In living patients, this has been evaluated in positron emission tomography studies using ligands such as 11C-DASB. This is supported by the loss of DASB binding in cortex and striatum following MCAO in rats, with a gradual recovery over 3 weeks (128), similar to the time course that we observed in post-ischemic mice (64). Using 11C-DASB to label 5-HTT, a reduced 5-HTT ratio between dorsal raphe/ventral striatum was seen in unmedicated depressed compared to healthy controls, suggesting reduced 5-HT innervation to this reward processing center (261). By contrast, no difference in 5-HTT levels was seen in recovered depressed subjects compared to controls (262), whereas alterations are seen in several brain areas of severely depressed patients (263). Restorative effects of antidepressant treatment on 5-HTT levels have also been reported. In depressed subjects, altered 5-HTT ratio between median raphe to bilateral habenula, amygdala-hippocampus and subgenual cingulate cortex predicted treatment response (264). In bipolar depression, lower levels of 5-HTT and 5-HT1A predicted response and remission to 8-wk lithium treatment (265). Taken together, these studies suggest that alterations in 5-HTT levels, perhaps due to altered 5-HT innervation, are associated with depression and response to SSRIs. However, these changes could simply reflect changes in 5-HTT expression level, rather than 5-HT innervation. Functional connectivity studies using fMRI with the raphe as a seed may provide addition evidence of impaired 5-HT projections, as raphe connectivity strength mirrors 5-HTT levels in healthy controls (266). Acute tryptophan depletion decreased functional connectivity of the raphe to right pregenual anterior cingulate cortex in SSRI-resistant depressed subjects, but increased raphe-left thalamus connectivity in SSRI-responders, suggesting that increased 5-HT innervation correlates with SSRI response (267). Taken together, these studies indicate a deficiency in 5-HT innervation occurs in major depression and can be modified by chronic treatment in SSRI-responders. The importance in behavior of these neuroplasticity changes remains to be addressed but developing strategies to enhance 5-HT neuroplasticity may provide a more robust antidepressant response. Using models of SSRI-resistant depression such as the cF1ko mice (10), it will be possible to elucidate whether changes in 5-HT axons associated with depression and anxiety are unresponsive to fluoxetine and develop alternative or augmentation therapies to efficiently enhance the activity of 5-HT system and axonal plasticity to treat SSRI-resistant patients.
Conclusion
Although not extensively studied, increasing evidence is indicating that deficiencies in 5-HT innervation associated with development, chronic stress or brain injury may lead to depression (10). Furthermore, the 5-HT system is capable of regenerating lost projections. Particularly after injury or chronic stress, 5-HT rewiring is induced during recovery (62), and can be enhanced by SSRI treatment or activation of 5-HT neurons (64, 66). While 5-HT rewiring correlates with recovery (66, 256), it remains to be directly addressed how important this mechanism is for recovery in rodent models. In humans, some research shows alterations in 5-HTT labeling in post-mortem OFC associated with major depression (32). Further studies are needed to determine what other brain regions might be affected, how early, and the effect of successful treatment on these projections.
Exactly how SSRIs might trigger reinnervation remains unclear. For example, 5-HT1A receptor-mediated induction of BDNF has been implicated in cortical synaptic plasticity, but whether BDNF mediates changes in innervation is unclear (188). However, abundant evidence indicates that several 5-HT receptors have actions to enhance synaptic plasticity and the formation of new synaptic connections. Direct activation of some of these receptors has been shown to mediate antidepressant actions in some tests and certain models of depression. However, it remains unclear how effective these compounds will be in human depression.
By coordinately targeting 5-HT activity, 5-HT release and 5-HT receptor-induced synaptic remodeling may provide a more effective strategy to treat depression, even in treatment-resistant depressed subjects.
Funding
This research was supported by a University of Ottawa Brain and Mind Research Institute Fellowship to FV-A and operating grant funding from the Canadian Institutes of Health Research to PA (PJT168948), and support for open access fees from the University of Ottawa Library.
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Statements
Author contributions
FV-A conceived and wrote the first draft, corrected revised version, and approved the final version. PA conceived and revised the first draft and finalized the manuscript. Both authors contributed to the article and approved the submitted version.
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.
References
1.
WHO. Depression and Other Common Mental Disorders: Global Health Estimates. (Geneva, Switzerland: World Health Organization). (2017).
2.
EttmanCKAbdallaSMCohenGHSampsonLVivierPMGaleaS. Prevalence of depression symptoms in US adults before and during the COVID-19 pandemic. JAMA Netw Open. (2020) 3:e2019686. 10.1001/jamanetworkopen.2020.19686
3.
Global Global Burden of Disease: Injury, Incidence, Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. (2018) 392:1789–858. 10.1016/S0140-6736(18)32279-7
4.
NierenbergAAFarabaughAHAlpertJEGordonJWorthingtonJJRosenbaumJFet al. Timing of onset of antidepressant response with fluoxetine treatment. Am J Psychiatry. (2000) 157:1423–8. 10.1176/appi.ajp.157.9.1423
5.
CiprianiAFurukawaTASalantiGGeddesJRHigginsJPChurchillRet al. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. (2009) 373:746–58. 10.1016/S0140-6736(09)60046-5
6.
CiprianiAFurukawaTASalantiGChaimaniAAtkinsonLZOgawaYet al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. (2018) 391:1357–66. 10.1016/S0140-6736(17)32802-7
7.
TrivediMHFavaMWisniewskiSRThaseMEQuitkinFWardenDet al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. (2006) 354:1243–52. 10.1056/NEJMoa052964
8.
ArtigasFBortolozziACeladaP. Can we increase speed and efficacy of antidepressant treatments? Part I: General aspects and monoamine-based strategies. Eur Neuropsychopharmacol. (2018) 28:445–56. 10.1016/j.euroneuro.2017.10.032
9.
KrishnanVNestlerEJ. The molecular neurobiology of depression. Nature. (2008) 455:894–902. 10.1038/nature07455
10.
Vahid-AnsariFZhangMZahraiAAlbertPR. Overcoming resistance to selective serotonin reuptake inhibitors: targeting serotonin, Serotonin-1A receptors and adult neuroplasticity. Front Neurosci. (2019) 13:404. 10.3389/fnins.2019.00404
11.
BortolozziACeladaPArtigasF. Novel therapeutic strategies in major depression: focus on RNAi and ketamine. Curr Pharm Des. (2014) 20:3848–60. 10.2174/13816128113196660137
12.
SchechterMDChanceWT. Non-specificity of “behavioral despair” as an animal model of depression. Eur J Pharmacol. (1979) 60:139–42. 10.1016/0014-2999(79)90212-7
13.
CryanJFMombereauCVassoutA. The tail suspension test as a model for assessing antidepressant activity: review of pharmacological and genetic studies in mice. Neurosci Biobehav Rev. (2005) 29:571–625. 10.1016/j.neubiorev.2005.03.009
14.
CastagnéVMoserPRouxSPorsoltRD. Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice. Curr Protoc Neurosci. (2011) 49:5–8. 10.1002/0471141755.ph0508s49
15.
CommonsKGCholaniansABBabbJAEhlingerDG. The rodent forced swim test measures stress-coping strategy, not depression-like behavior. ACS Chem Neurosci. (2017) 8:955–60. 10.1021/acschemneuro.7b00042
16.
CalhoonGGTyeKM. Resolving the neural circuits of anxiety. Nat Neurosci. (2015) 18:1394–404. 10.1038/nn.4101
17.
GururajanAReifACryanJFSlatteryDA. The future of rodent models in depression research. Nat Rev Neurosci. (2019) 20:686–701. 10.1038/s41583-019-0221-6
18.
RamakerMJDulawaSC. Identifying fast-onset antidepressants using rodent models. Mol Psychiatry. (2017) 22:656–65. 10.1038/mp.2017.36
19.
AlbertPRVahid-AnsariFLuckhartC. Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: pivotal role of pre- and post-synaptic 5-HT1A receptor expression. Front Behav Neurosci. (2014) 8:199. 10.3389/fnbeh.2014.00199
20.
MuirJLopezJBagotRC. Wiring the depressed brain: optogenetic and chemogenetic circuit interrogation in animal models of depression. Neuropsychopharmacology. (2019) 44:1013–26. 10.1038/s41386-018-0291-6
21.
HareBDDumanRS. Prefrontal cortex circuits in depression and anxiety: contribution of discrete neuronal populations and target regions. Mol Psychiatry. (2020) 25:2742–58. 10.1038/s41380-020-0685-9
22.
BiselliTLangeSSSablottnyLSteffenJWaltherA. Optogenetic and chemogenetic insights into the neurocircuitry of depression-like behaviour: a systematic review. Eur J Neurosci. (2021) 53:9–38. 10.1111/ejn.14603
23.
BittarTPLabonteB. Functional contribution of the medial prefrontal circuitry in major depressive disorder and stress-induced depressive-like behaviors. Front Behav Neurosci. (2021) 15:699592. 10.3389/fnbeh.2021.699592
24.
HeningerGRDelgadoPLCharneyDS. The revised monoamine theory of depression: a modulatory role for monoamines, based on new findings from monoamine depletion experiments in humans. Pharmacopsychiatry. (1996) 29:2–11. 10.1055/s-2007-979535
25.
BlierPDe MontignyC. Possible serotonergic mechanisms underlying the antidepressant and anti- obsessive-compulsive disorder responses. Biol Psychiatry. (1998) 44:313–23. 10.1016/S0006-3223(98)00114-0
26.
ArangoVUnderwoodMDBoldriniMTamirHKassirSAHsiungSet al. Serotonin 1A receptors, serotonin transporter binding and serotonin transporter mRNA expression in the brainstem of depressed suicide victims. Neuropsychopharmacology. (2001) 25:892–903. 10.1016/S0893-133X(01)00310-4
27.
CervoLCanettaACalcagnoEBurbassiSSacchettiGCacciaSet al. Genotype-dependent activity of tryptophan hydroxylase-2 determines the response to citalopram in a mouse model of depression. J Neurosci. (2005) 25:8165–72. 10.1523/JNEUROSCI.1816-05.2005
28.
ZhangXGainetdinovRRBeaulieuJMSotnikovaTDBurchLHWilliamsRBet al. Loss-of-function mutation in tryptophan hydroxylase-2 identified in unipolar major depression. Neuron. (2005) 45:11–6. 10.1016/j.neuron.2004.12.014
29.
Richardson-JonesJWCraigeCPGuiardBPStephenAMetzgerKLKungHFet al. 5-HT(1A) autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron. (2010) 65:40–52. 10.1016/j.neuron.2009.12.003
30.
JacobsenJPMedvedevIOCaronMG. The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse. Philos Trans R Soc Lond B Biol Sci. (2012) 367:2444–59. 10.1098/rstb.2012.0109
31.
MatthewsPRHarrisonPJ. A morphometric, immunohistochemical, and in situ hybridization study of the dorsal raphe nucleus in major depression, bipolar disorder, schizophrenia, and suicide. J Affect Disord. (2012) 137:125–34. 10.1016/j.jad.2011.10.043
32.
RajkowskaGMahajanGLegutkoBChallagundlaLGriswoldMAlbertPRet al. Length of axons expressing the serotonin transporter in orbitofrontal cortex is lower with age in depression. Neuroscience. (2017) 359:30–9. 10.1016/j.neuroscience.2017.07.006
33.
RiadMKobertADescarriesLBoyeSRomprePPLacailleJC. Chronic fluoxetine rescues changes in plasma membrane density of 5-HT1A autoreceptors and serotonin transporters in the olfactory bulbectomy rodent model of depression. Neuroscience. (2017) 356:78–88. 10.1016/j.neuroscience.2017.05.021
34.
NazziSMaddaloniGPratelliMPasqualettiM. Fluoxetine induces morphological rearrangements of serotonergic fibers in the hippocampus. ACS Chem Neurosci. (2019) 10:3218–24. 10.1021/acschemneuro.8b00655
35.
PratelliMPasqualettiM. Serotonergic neurotransmission manipulation for the understanding of brain development and function: Learning from Tph2 genetic models. Biochimie. (2019) 161:3–14. 10.1016/j.biochi.2018.11.016
36.
PrakashNStarkCJKeislerMNLuoLDer-AvakianADulcisD. Serotonergic plasticity in the dorsal raphe nucleus characterizes susceptibility and resilience to anhedonia. J Neurosci. (2020) 40:569–84. 10.1523/JNEUROSCI.1802-19.2019
37.
HarmerCJ. Serotonin and emotional processing: does it help explain antidepressant drug action?Neuropharmacology. (2008) 55:1023–8. 10.1016/j.neuropharm.2008.06.036
38.
HirschfeldRM. History and evolution of the monoamine hypothesis of depression. J Clin Psychiatry. (2000) 61:4–6.
39.
CowenPJ. Serotonin and depression: pathophysiological mechanism or marketing myth?Trends Pharmacol Sci. (2008) 29:433–6. 10.1016/j.tips.2008.05.004
40.
AlbertPRBenkelfatCDescarriesL. The neurobiology of depression–revisiting the serotonin hypothesis. I Cellular and molecular mechanisms. Philos Trans R Soc Lond B Biol Sci. (2012) 367:2378–81. 10.1098/rstb.2012.0190
41.
TorkI. Anatomy of the serotonergic system. Ann N Y Acad Sci. (1990) 600:9–3410.1111/j.1749-6632.1990.tb16870.x
42.
VertesRP. A PHA-L analysis of ascending projections of the dorsal raphe nucleus in the rat. J Comp Neurol. (1991) 313:643–68. 10.1002/cne.903130409
43.
VertesRPFortinWJCraneAM. Projections of the median raphe nucleus in the rat. J Comp Neurol. (1999) 407:555–82. 10.1002/(SICI)1096-9861(19990517)407:4<555::AID-CNE7>3.0.CO;2-E
44.
WaltherDJPeterJUBashammakhSHortnaglHVoitsMFinkHet al. Synthesis of serotonin by a second tryptophan hydroxylase isoform. Science. (2003) 299:76. 10.1126/science.1078197
45.
Bach-MizrachiHUnderwoodMDKassirSABakalianMJSibilleETamirHet al. Neuronal tryptophan hydroxylase mRNA expression in the human dorsal and median raphe nuclei: major depression and suicide. Neuropsychopharmacology. (2006) 31:814–24. 10.1038/sj.npp.1300897
46.
LeschKPAraragiNWaiderJVan Den HoveDGutknechtL. Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour. Philos Trans R Soc Lond B Biol Sci. (2012) 367:2426–43. 10.1098/rstb.2012.0039
47.
AndersonIMTomensonBM. The efficacy of selective serotonin re-uptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants. J Psychopharmacol. (1994) 8:238–49. 10.1177/026988119400800407
48.
StahlSM. Mechanism of action of serotonin selective reuptake inhibitors. Serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord. (1998) 51:215–35. 10.1016/S0165-0327(98)00221-3
49.
AndradeRHaj-DahmaneS. Serotonin neuron diversity in the dorsal raphe. ACS Chem Neurosci. (2013) 4:22–5. 10.1021/cn300224n
50.
CommonsKG. Dorsal raphe organization. J Chem Neuroanat. (2020) 110:101868. 10.1016/j.jchemneu.2020.101868
51.
OkatyBWSturrockNEscobedo LozoyaYChangYSenftRALyonKAet al. A single-cell transcriptomic and anatomic atlas of mouse dorsal raphe Pet1 neurons. Elife. (2020) 9:e55523. 10.7554/eLife.55523
52.
CalizoLHAkanwaAMaXPanYZLemosJCCraigeCet al. Raphe serotonin neurons are not homogenous: electrophysiological, morphological and neurochemical evidence. Neuropharmacology. (2011) 61:524–43. 10.1016/j.neuropharm.2011.04.008
53.
KiyasovaVBonnavionPScotto-LomasseseSFabreVSahlyITroncheFet al. A subpopulation of serotonergic neurons that do not express the 5-HT1A autoreceptor. ACS Chem Neurosci. (2013) 4:89–95. 10.1021/cn300157s
54.
AmilhonBLepicardERenoirTMongeauRPopaDPoirelOet al. VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety. J Neurosci. (2010) 30:2198–210. 10.1523/JNEUROSCI.5196-09.2010
55.
CommonsKG. Ascending serotonin neuron diversity under two umbrellas. Brain Struct Funct. (2016) 221:3347–60. 10.1007/s00429-015-1176-7
56.
RenJFriedmannDXiongJLiuCDFergusonBRWeerakkodyTet al. Anatomically defined and functionally distinct dorsal raphe serotonin sub-systems. Cell. (2018) 175:472–87e420. 10.1016/j.cell.2018.07.043
57.
BjorklundALindvallO. Regeneration of normal terminal innervation patterns by central noradrenergic neurons after 5,7-dihydroxytryptamine-induced axotomy in the adult rat. Brain Res. (1979) 171:271–93. 10.1016/0006-8993(79)90333-0
58.
ZhouFCAzmitiaEC. Induced homotypic sprouting of serotonergic fibers in hippocampus. II An immunocytochemistry study. Brain Res. (1986) 373:337–48. 10.1016/0006-8993(86)90348-3
59.
BlueMEMolliverME. 6-Hydroxydopamine induces serotonergic axon sprouting in cerebral cortex of newborn rat. Brain Res. (1987) 429:255–69. 10.1016/0165-3806(87)90106-4
60.
FrankfurtMBeaudetA. Reinnervation of dopamine neurons by regenerating serotonin axons in the rat medial zona incerta. A combined radioautographic and immunocytochemical ultrastructural study. Exp Brain Res. (1988) 72:473–80. 10.1007/BF00250592
61.
DescarriesLSoghomonianJJGarciaSDoucetGBrunoJP. Ultrastructural analysis of the serotonin hyperinnervation in adult rat neostriatum following neonatal dopamine denervation with 6-hydroxydopamine. Brain Res. (1992) 569:1–13. 10.1016/0006-8993(92)90363-E
62.
JinYDoughertySEWoodKSunLCudmoreRHAbdallaAet al. Regrowth of serotonin axons in the adult mouse brain following injury. Neuron. (2016) 91:748–62. 10.1016/j.neuron.2016.07.024
63.
KajsturaTJDoughertySELindenDJ. Serotonin axons in the neocortex of the adult female mouse regrow after traumatic brain injury. J Neurosci Res. (2018) 96:512–26. 10.1002/jnr.24059
64.
ZahraiAVahid-AnsariFDaigleMAlbertPR. Fluoxetine-induced recovery of serotonin and norepinephrine projections in a mouse model of post-stroke depression. Transl Psychiatry. (2020) 10:334. 10.1038/s41398-020-01008-9
65.
LiuYNakamuraS. Stress-induced plasticity of monoamine axons. Front Biosci. (2006) 11:1794–801. 10.2741/1923
66.
VeerakumarAChallisCGuptaPDaJUpadhyayABeckSGet al. Antidepressant-like effects of cortical deep brain stimulation coincide with pro-neuroplastic adaptations of serotonin systems. Biol Psychiatry. (2014) 76:203–12. 10.1016/j.biopsych.2013.12.009
67.
WihanJGroschJKalinichenkoLSMullerCPWinklerJKohlZ. Layer-specific axonal degeneration of serotonergic fibers in the prefrontal cortex of aged A53T alpha-synuclein-expressing mice. Neurobiol Aging. (2019) 80:29–37. 10.1016/j.neurobiolaging.2019.03.014
68.
GagnonDGregoireLDi PaoloTParentM. Serotonin hyperinnervation of the striatum with high synaptic incidence in parkinsonian monkeys. Brain Struct Funct. (2016) 221:3675–91. 10.1007/s00429-015-1125-5
69.
BeaudetADescarriesL. Quantitative data on serotonin nerve terminals in adult rat neocortex. Brain Res. (1976) 111:301–9. 10.1016/0006-8993(76)90775-7
70.
BeaudetADescarriesL. The fine structure of central serotonin neurons. J Physiol (Paris). (1981) 77:193–203.
71.
SteinbuschHW. Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience. (1981) 6:557–618. 10.1016/0306-4522(81)90146-9
72.
BarnesNMAhernGPBecamelCBockaertJCamilleriMChaumont-DubelSet al. International union of basic and clinical pharmacology. CX classification of receptors for 5-hydroxytryptamine; pharmacology and function. Pharmacol Rev. (2021) 73:310–520. 10.1124/pr.118.015552
73.
LidovHGMolliverME. An immunohistochemical study of serotonin neuron development in the rat: ascending pathways and terminal fields. Brain Res Bull. (1982) 8:389–430. 10.1016/0361-9230(82)90077-6
74.
KiyasovaVGasparP. Development of raphe serotonin neurons from specification to guidance. Eur J Neurosci. (2011) 34:1553–62. 10.1111/j.1460-9568.2011.07910.x
75.
FitoussiADellu-HagedornFDe DeurwaerdereP. Monoamines tissue content analysis reveals restricted and site-specific correlations in brain regions involved in cognition. Neuroscience. (2013) 255:233–45. 10.1016/j.neuroscience.2013.09.059
76.
DenerisEGasparP. Serotonin neuron development: shaping molecular and structural identities. Wiley Interdiscip Rev Dev Biol. (2018) 7:e301. 10.1002/wdev.301
77.
OkatyBWCommonsKGDymeckiSM. Embracing diversity in the 5-HT neuronal system. Nat Rev Neurosci. (2019) 20:397–424. 10.1038/s41583-019-0151-3
78.
DonovanLJSpencerWCKittMMEastmanBALoburKJJiaoKet al. Lmx1b is required at multiple stages to build expansive serotonergic axon architectures. Elife. (2019) 8:e48788. 10.7554/eLife.48788
79.
DonovanSLMamounasLAAndrewsAMBlueMEMccaslandJS. GAP-43 is critical for normal development of the serotonergic innervation in forebrain. J Neurosci. (2002) 22:3543–52. 10.1523/JNEUROSCI.22-09-03543.2002
80.
FournetVJanyMFabreVChaliFOrsalDSchweitzerAet al. The deletion of the microtubule-associated STOP protein affects the serotonergic mouse brain network. J Neurochem. (2010) 115:1579–94. 10.1111/j.1471-4159.2010.07064.x
81.
FournetVSchweitzerAChevarinCDeloulmeJCHamonMGirosBet al. The deletion of STOP/MAP6 protein in mice triggers highly altered mood and impaired cognitive performances. J Neurochem. (2012) 121:99–114. 10.1111/j.1471-4159.2011.07615.x
82.
FenstermakerAGPrasadAABecharaAAdolfsYTissirFGoffinetAet al. Wnt/planar cell polarity signaling controls the anterior-posterior organization of monoaminergic axons in the brainstem. J Neurosci. (2010) 30:16053–64. 10.1523/JNEUROSCI.4508-10.2010
83.
BagriAMarinOPlumpASMakJPleasureSJRubensteinJLet al. Slit proteins prevent midline crossing and determine the dorsoventral position of major axonal pathways in the mammalian forebrain. Neuron. (2002) 33:233–48. 10.1016/S0896-6273(02)00561-5
84.
Lopez-BenditoGFlamesNMaLFouquetCDi MeglioTChedotalAet al. Robo1 and Robo2 cooperate to control the guidance of major axonal tracts in the mammalian forebrain. J Neurosci. (2007) 27:3395–407. 10.1523/JNEUROSCI.4605-06.2007
85.
KatoriSHamadaSNoguchiYFukudaEYamamotoTYamamotoHet al. Protocadherin-alpha family is required for serotonergic projections to appropriately innervate target brain areas. J Neurosci. (2009) 29:9137–47. 10.1523/JNEUROSCI.5478-08.2009
86.
FlahertyEManiatisT. The role of clustered protocadherins in neurodevelopment and neuropsychiatric diseases. Curr Opin Genet Dev. (2020) 65:144–50. 10.1016/j.gde.2020.05.041
87.
ChenWVNwakezeCLDennyCAO'KeeffeSRiegerMAMountoufarisGet al. Pcdhalphac2 is required for axonal tiling and assembly of serotonergic circuitries in mice. Science. (2017) 356:406–11. 10.1126/science.aal3231
88.
VadodariaKCJiYSkimeMPaquolaACNelsonTHall-FlavinDet al. Altered serotonergic circuitry in SSRI-resistant major depressive disorder patient-derived neurons. Mol Psychiatry. (2019) 24:808–18. 10.1038/s41380-019-0377-5
89.
Roberson-NayRLapatoDMWolenARLancasterEEWebbBTVerhulstBet al. An epigenome-wide association study of early-onset major depression in monozygotic twins. Transl Psychiatry. (2020) 10:301. 10.1038/s41398-020-00984-2
90.
DahlströmAFuxeK. Evidence for the existence of monoamine-containing neurons in the central nervous system. I demonstration of monoamines in the cell bodies of brain stem neurons. Acta Physiol Scand Suppl. (1964) 232:231–55.
91.
DescarriesLRiadMParentM. Ultrastructure of the serotonin innervation in the mammalian central nervous system. Handb Behav Neurosci. (2010) 21:65–101. 10.1016/S1569-7339(10)70072-2
92.
NielsenKBraskDKnudsenGMAznarS. Immunodetection of the serotonin transporter protein is a more valid marker for serotonergic fibers than serotonin. Synapse. (2006) 59:270–6. 10.1002/syn.20240
93.
BrownPMolliverME. Dual serotonin (5-HT) projections to the nucleus accumbens core and shell: relation of the 5-HT transporter to amphetamine-induced neurotoxicity. J Neurosci. (2000) 20:1952–63. 10.1523/JNEUROSCI.20-05-01952.2000
94.
JanušonisS. Serotonin dynamics in and around the central nervous system: is autism solvable without fundamental insights?Int J Dev Neurosci. (2014) 39:9–15. 10.1016/j.ijdevneu.2014.05.009
95.
JanušonisS. Serotonin in space: understanding single fibers. ACS Chem Neurosci. (2017) 8:893–6. 10.1021/acschemneuro.6b00417
96.
LebrandCCasesOAdelbrechtCDoyeAAlvarezCEl MestikawySet al. Transient uptake and storage of serotonin in developing thalamic neurons. Neuron. (1996) 17:823–35. 10.1016/S0896-6273(00)80215-9
97.
Narboux-NemeNPavoneLMAvalloneLZhuangXGasparP. Serotonin transporter transgenic (SERTcre) mouse line reveals developmental targets of serotonin specific reuptake inhibitors (SSRIs). Neuropharmacology. (2008) 55:994–1005. 10.1016/j.neuropharm.2008.08.020
98.
SulzerDEdwardsRH. Antidepressants and the monoamine masquerade. Neuron. (2005) 46:1–2. 10.1016/j.neuron.2005.03.013
99.
ZhouFMLiangYSalasRZhangLDe BiasiMDaniJA. Corelease of dopamine and serotonin from striatal dopamine terminals. Neuron. (2005) 46:65–74. 10.1016/j.neuron.2005.02.010
100.
GantzSCLevittESLlamosasNNeveKAWilliamsJT. Depression of serotonin synaptic transmission by the dopamine precursor L-DOPA. Cell Rep. (2015) 12:944–54. 10.1016/j.celrep.2015.07.005
101.
BeaudetADescarriesL. The monoamine innervation of rat cerebral cortex: synaptic and nonsynaptic axon terminals. Neuroscience. (1978) 3:851–60. 10.1016/0306-4522(78)90115-X
102.
FuxeKDahlströmAHöistadMMarcellinoDJanssonARiveraAet al. From the Golgi-Cajal mapping to the transmitter-based characterization of the neuronal networks leading to two modes of brain communication: wiring and volume transmission. Brain Res Rev. (2007) 55:17–54. 10.1016/j.brainresrev.2007.02.009
103.
FuxeKDahlstromABJonssonGMarcellinoDGuesciniMDamMet al. The discovery of central monoamine neurons gave volume transmission to the wired brain. Prog Neurobiol. (2010) 90:82–100. 10.1016/j.pneurobio.2009.10.012
104.
BangSJJensenPDymeckiSMCommonsKG. Projections and interconnections of genetically defined serotonin neurons in mice. Eur J Neurosci. (2012) 35:85–96. 10.1111/j.1460-9568.2011.07936.x
105.
HainerCMosienkoVKoutsikouSCrookJJGlossBKasparovSet al. Beyond gene inactivation: evolution of tools for analysis of serotonergic circuitry. ACS Chem Neurosci. (2015) 6:1116–29. 10.1021/acschemneuro.5b00045
106.
LuoLCallawayEMSvobodaK. Genetic dissection of neural circuits: a decade of progress. Neuron. (2018) 98:256–81. 10.1016/j.neuron.2018.03.040
107.
Pollak DorocicIFurthDXuanYJohanssonYPozziLSilberbergGet al. A whole-brain atlas of inputs to serotonergic neurons of the dorsal and median raphe nuclei. Neuron. (2014) 83:663–78. 10.1016/j.neuron.2014.07.002
108.
WeissbourdBRenJDeloachKEGuenthnerCJMiyamichiKLuoL. Presynaptic partners of dorsal raphe serotonergic and GABAergic neurons. Neuron. (2014) 83:645–62. 10.1016/j.neuron.2014.06.024
109.
FernandezSPCauliBCabezasCMuzerelleAPoncerJCGasparP. Multiscale single-cell analysis reveals unique phenotypes of raphe 5-HT neurons projecting to the forebrain. Brain Struct Funct. (2016) 221:4007–25. 10.1007/s00429-015-1142-4
110.
MuzerelleAScotto-LomasseseSBernardJFSoiza-ReillyMGasparP. Conditional anterograde tracing reveals distinct targeting of individual serotonin cell groups (B5-B9) to the forebrain and brainstem. Brain Struct Funct. (2016) 221:535–61. 10.1007/s00429-014-0924-4
111.
ZhouLLiuMZLiQDengJMuDSunYG. Organization of functional long-range circuits controlling the activity of serotonergic neurons in the dorsal raphe nucleus. Cell Rep. (2017) 18:3018–32. 10.1016/j.celrep.2017.02.077
112.
Van BockstaeleEJBiswasAPickelVM. Topography of serotonin neurons in the dorsal raphe nucleus that send axon collaterals to the rat prefrontal cortex and nucleus accumbens. Brain Res. (1993) 624:188–98. 10.1016/0006-8993(93)90077-Z
113.
GagnonDParentM. Distribution of VGLUT3 in highly collateralized axons from the rat dorsal raphe nucleus as revealed by single-neuron reconstructions. PLoS One. (2014) 9:e87709. 10.1371/journal.pone.0087709
114.
BelmerAPatkarOLPitmanKMBartlettSE. Serotonergic Neuroplasticity in Alcohol Addiction. Brain Plast. (2016) 1:177–206. 10.3233/BPL-150022
115.
BelmerAKlenowskiPMPatkarOLBartlettSE. Mapping the connectivity of serotonin transporter immunoreactive axons to excitatory and inhibitory neurochemical synapses in the mouse limbic brain. Brain Struct Funct. (2017) 222:1297–314. 10.1007/s00429-016-1278-x
116.
BakerKGHallidayGMHalaszPHornungJPGeffenLBCottonRGet al. Cytoarchitecture of serotonin-synthesizing neurons in the pontine tegmentum of the human brain. Synapse. (1991) 7:301–20. 10.1002/syn.890070407
117.
HornungJP. The human raphe nuclei and the serotonergic system. J Chem Neuroanat. (2003) 26:331–43. 10.1016/j.jchemneu.2003.10.002
118.
AzmitiaECSinghJSWhitaker-AzmitiaPM. Increased serotonin axons (immunoreactive to 5-HT transporter) in postmortem brains from young autism donors. Neuropharmacology. (2011) 60:1347–54. 10.1016/j.neuropharm.2011.02.002
119.
IshikawaJIshikawaANakamuraS. Interferon-alpha reduces the density of monoaminergic axons in the rat brain. Neuroreport. (2007) 18:137–40. 10.1097/WNR.0b013e328010231a
120.
AgnatiLFFuxeKZoliMOziniIToffanoGFerragutiF. A correlation analysis of the regional distribution of central enkephalin and beta-endorphin immunoreactive terminals and of opiate receptors in adult and old male rats. Evidence for the existence of two main types of communication in the central nervous system: the volume transmission and the wiring transmission. Acta Physiol Scand. (1986) 128:201–7. 10.1111/j.1748-1716.1986.tb07967.x
121.
JenningsKA. A comparison of the subsecond dynamics of neurotransmission of dopamine and serotonin. ACS Chem Neurosci. (2013) 4:704–14. 10.1021/cn4000605
122.
BjelkeBStrömbergIO'ConnorWTAndbjerBAgnatiLFFuxeK. Evidence for volume transmission in the dopamine denervated neostriatum of the rat after a unilateral nigral 6-OHDA microinjection. Studies with systemic D-amphetamine treatment. Brain Res. (1994) 662:11–24. 10.1016/0006-8993(94)90791-9
123.
BjelkeBEnglandRNicholsonCRiceMELindbergJZoliMet al. Long distance pathways of diffusion for dextran along fibre bundles in brain. Relevance for volume transmission. Neuroreport. (1995) 6:1005–9. 10.1097/00001756-199505090-00014
124.
SulzerDCraggSJRiceME. Striatal dopamine neurotransmission: regulation of release and uptake. Basal Ganglia. (2016) 6:123–48. 10.1016/j.baga.2016.02.001
125.
PostMRSulzerD. The chemical tools for imaging dopamine release. Cell Chem Biol. (2021) 28:748–64. 10.1016/j.chembiol.2021.04.005
126.
ViziESFeketeAKarolyRMikeA. Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment. Br J Pharmacol. (2010) 160:785–809. 10.1111/j.1476-5381.2009.00624.x
127.
Borroto-EscuelaDOPerez De La MoraMMangerPNarvaezMBeggiatoSCrespo-RamirezMet al. Brain dopamine transmission in health and parkinson's disease: modulation of synaptic transmission and plasticity through volume transmission and dopamine heteroreceptors. Front Synaptic Neurosci. (2018) 10:20. 10.3389/fnsyn.2018.00020
128.
MartinASzczupakBGomez-VallejoVPlazaSPadroDCanoAet al. PET imaging of serotoninergic neurotransmission with [(11)C]DASB and [(18)F]altanserin after focal cerebral ischemia in rats. J Cereb Blood Flow Metab. (2013) 33:1967–75. 10.1038/jcbfm.2013.156
129.
MartinKASpuhlerIA. The fine structure of the dopaminergic innervation of area 10 of macaque prefrontal cortex. Eur J Neurosci. (2013) 37:1061–71. 10.1111/ejn.12124
130.
RiceMECraggSJ. Dopamine spillover after quantal release: rethinking dopamine transmission in the nigrostriatal pathway. Brain Res Rev. (2008) 58:303–13. 10.1016/j.brainresrev.2008.02.004
131.
FuxeKUngerstedtU. Histochemical, biochemical and functional studies on central monoamine neurons after acute and chronic amphetamine administration. In: CostaEGarattiniS editors. Amphetamines and Related Compounds.New York, NY: Raven Press (1970). p. 257–288.
132.
FuxeKHokfeltTJonssonGUngerstedtU. Fluorescence microscopy in neuroanatomy. In: NautaWJHEbbessonSOE editors. Contemporary Research Methods in Neuroanatomy. Berlin: Springer-Verlag (1970). p. 275–314.
133.
DescarriesLWatkinsKCGarciaSBeaudetA. The serotonin neurons in nucleus raphe dorsalis of adult rat: a light and electron microscope radioautographic study. J Comp Neurol. (1982) 207:239–54. 10.1002/cne.902070305
134.
BuninMAWightmanRM. Quantitative evaluation of 5-hydroxytryptamine (serotonin) neuronal release and uptake: an investigation of extrasynaptic transmission. J Neurosci. (1998) 18:4854–60. 10.1523/JNEUROSCI.18-13-04854.1998
135.
BuninMAWightmanRM. Paracrine neurotransmission in the CNS: involvement of 5-HT. Trends Neurosci. (1999) 22:377–82. 10.1016/S0166-2236(99)01410-1
136.
ColganLACavoloSLCommonsKGLevitanES. Action potential-independent and pharmacologically unique vesicular serotonin release from dendrites. J Neurosci. (2012) 32:15737–46. 10.1523/JNEUROSCI.0020-12.2012
137.
QuentinEBelmerAMaroteauxL. Somato-dendritic regulation of raphe serotonin neurons; a key to antidepressant action. Front Neurosci. (2018) 12:982. 10.3389/fnins.2018.00982
138.
Vahid-AnsariFDaigleMManziniMCTanakaKFHenRGeddesSDet al. Abrogated Freud-1/Cc2d1a repression of 5-HT1A autoreceptors induces fluoxetine-resistant anxiety/depression-like behavior. J Neurosci. (2017) 37:11967–78. 10.1523/JNEUROSCI.1668-17.2017
139.
BelmerAQuentinEDiazSLGuiardBPFernandezSPDolySet al. Positive regulation of raphe serotonin neurons by serotonin 2B receptors. Neuropsychopharmacology. (2018) 43:1623–32. 10.1038/s41386-018-0013-0
140.
AndradeRHuerecaDLyonsJGAndradeEMMcgregorKM. 5-HT1A receptor-mediated autoinhibition and the control of serotonergic cell firing. ACS Chem Neurosci. (2015) 6:1110–5. 10.1021/acschemneuro.5b00034
141.
HikimaTLeeCRWitkovskyPCheslerJIchtchenkoKRiceME. Activity-dependent somatodendritic dopamine release in the substantia nigra autoinhibits the releasing neuron. Cell Rep. (2021) 35:108951. 10.1016/j.celrep.2021.108951
142.
WallaceJALauderJM. Development of the serotonergic system in the rat embryo: an immunocytochemical study. Brain Res Bull. (1983) 10:459–79. 10.1016/0361-9230(83)90144-2
143.
AitkenARTorkI. Early development of serotonin-containing neurons and pathways as seen in wholemount preparations of the fetal rat brain. J Comp Neurol. (1988) 274:32–47. 10.1002/cne.902740105
144.
DinopoulosADoriIParnavelasJG. The serotonin innervation of the basal forebrain shows a transient phase during development. Brain Res Dev Brain Res. (1997) 99:38–52. 10.1016/S0165-3806(96)00198-8
145.
García-GonzálezDKhodosevichKWatanabeYRollenhagenALübkeJHMonyerH. Serotonergic projections govern postnatal neuroblast migration. Neuron. (2017) 94:534–549e539. 10.1016/j.neuron.2017.04.013
146.
SarginDJeoungHSGoodfellowNMLambeEK. Serotonin regulation of the prefrontal cortex: cognitive relevance and the impact of developmental perturbation. ACS Chem Neurosci. (2019) 10:3078–93. 10.1021/acschemneuro.9b00073
147.
Narboux-NemeNAngenardGMosienkoVKlempinFPitychoutisPMDenerisEet al. Postnatal growth defects in mice with constitutive depletion of central serotonin. ACS Chem Neurosci. (2013) 4:171–81. 10.1021/cn300165x
148.
MaddaloniGBerteroAPratelliMBarsottiNBoonstraAGiorgiAet al. Development of serotonergic fibers in the post-natal mouse brain. Front Cell Neurosci. (2017) 11:202. 10.3389/fncel.2017.00202
149.
PratelliMMigliariniSPelosiBNapolitanoFUsielloAPasqualettiM. Perturbation of serotonin homeostasis during adulthood affects serotonergic neuronal circuitry. eNeuro. (2017) 4:ENEURO.0376-16.2017. 10.1523/ENEURO.0376-16.2017
150.
TeissierASoiza-ReillyMGasparP. Refining the role of 5-HT in postnatal development of brain circuits. Front Cell Neurosci. (2017) 11:139. 10.3389/fncel.2017.00139
151.
ChenXYeRGargusJJBlakelyRDDobrenisKSzeJY. Disruption of transient serotonin accumulation by non-serotonin-producing neurons impairs cortical map development. Cell Rep. (2015) 10:346–58. 10.1016/j.celrep.2014.12.033
152.
YanWWilsonCCHaringJH. Effects of neonatal serotonin depletion on the development of rat dentate granule cells. Brain Res Dev Brain Res. (1997) 98:177–84. 10.1016/S0165-3806(96)00176-9
153.
VitalisTCasesOGilliesKHanounNHamonMSeifIet al. Interactions between TrkB signaling and serotonin excess in the developing murine somatosensory cortex: a role in tangential and radial organization of thalamocortical axons. J Neurosci. (2002) 22:4987–5000. 10.1523/JNEUROSCI.22-12-04987.2002
154.
RiccioOJacobshagenMGoldingBVutskitsLJabaudonDHornungJPet al. Excess of serotonin affects neocortical pyramidal neuron migration. Transl Psychiatry. (2011) 1:e47. 10.1038/tp.2011.49
155.
TodaTHommaDTokuokaHHayakawaISugimotoYIchinoseHet al. Birth regulates the initiation of sensory map formation through serotonin signaling. Dev Cell. (2013) 27:32–46. 10.1016/j.devcel.2013.09.002
156.
VicenziSFoaLGasperiniRJ. Serotonin functions as a bidirectional guidance molecule regulating growth cone motility. Cell Mol Life Sci. (2021) 78:2247–62. 10.1007/s00018-020-03628-2
157.
HannonJHoyerD. Molecular biology of 5-HT receptors. Behav Brain Res. (2008) 195:198–213. 10.1016/j.bbr.2008.03.020
158.
DavalGVergeDBecerrilAGozlanHSpampinatoUHamonM. Transient expression of 5-HT1A receptor binding sites in some areas of the rat CNS during postnatal development. Int J Dev Neurosci. (1987) 5:171–80. 10.1016/0736-5748(87)90027-X
159.
Del OlmoEDiazAGuirao-PineyroMDel ArcoCPascualJPazosA. Transient localization of 5-HT1A receptors in human cerebellum during development. Neurosci Lett. (1994) 166:149–52. 10.1016/0304-3940(94)90472-3
160.
MiquelMCKiaHKBoniCDoucetEDavalGMatthiessenLet al. Postnatal development and localization of 5-HT1A receptor mRNA in rat forebrain and cerebellum. Brain Res Develop Brain Res. (1994) 80:149–57. 10.1016/0165-3806(94)90099-X
161.
Del OlmoELopez-GimenezJFVilaroMTMengodGPalaciosJMPazosA. Early localization of mRNA coding for 5-HT1A receptors in human brain during development. Brain Res Mol Brain Res. (1998) 60:123–6. 10.1016/S0169-328X(98)00149-1
162.
HamonMGozlanHMestikawySEmeritMBBolañosFSchechterL. The central 5-HT1A receptors: pharmacological, biochemical, functional, and regulatory properties. Ann N Y Acad Sci. (1990) 600:114–29. 10.1111/j.1749-6632.1990.tb16877
163.
HoyerDSchoeffterPWaeberCPalaciosJM. Serotonin 5-HT1D receptors. Ann N Y Acad Sci. (1990) 600:168–181.
164.
BurnetPWEastwoodSLLaceyKHarrisonPJ. The distribution of 5-HT1A and 5-HT2A receptor mRNA in human brain. Brain Res. (1995) 676:157–168.
165.
SoteloCCholleyBMestikawySGozlanHHamonM. 1990. Direct immunohistochemical evidence of the existence of 5-HT1A autoreceptors on serotoninergic neurons in the midbrain raphe nuclei. Eur J Neurosci. (1990) 2:1144–54. 10.1111/j.1460-9568.1990.tb00026.x
166.
PompeianoMPalaciosJMMengodG. Distribution and cellular localization of mRNA coding for 5-HT1A receptor in the rat brain: correlation with receptor binding. J Neurosci. (1992) 12:440–53. 10.1523/JNEUROSCI.12-02-00440.1992
167.
HallHLundkvistCHalldinCFardeLPikeVWMccarronJAet al. Autoradiographic localization of 5-HT1A receptors in the post-mortem human brain using [3H]WAY-100635 and [11C]way-100635. Brain Res. (1997) 745:96–108. 10.1016/S0006-8993(96)01131-6
168.
MengodGPalaciosJMCortesR. Cartography of 5-HT1A and 5-HT2A receptor subtypes in prefrontal cortex and its projections. ACS Chem Neurosci. (2015) 6:1089–98. 10.1021/acschemneuro.5b00023
169.
AzmitiaECGannonPJKheckNMWhitaker-AzmitiaPM. Cellular localization of the 5-HT1A receptor in primate brain neurons and glial cells. Neuropsychopharmacology. (1996) 14:35–46. 10.1016/S0893-133X(96)80057-1
170.
MerzakAKoochekpourSFillionMPFillionGPilkingtonGJ. Expression of serotonin receptors in human fetal astrocytes and glioma cell lines: a possible role in glioma cell proliferation and migration. Brain Res Mol Brain Res. (1996) 41:1–7. 10.1016/0169-328X(96)00058-7
171.
KikuokaRMiyazakiIKubotaNMaedaMKagawaDMoriyamaMet al. Mirtazapine exerts astrocyte-mediated dopaminergic neuroprotection. Sci Rep. (2020) 10:20698. 10.1038/s41598-020-77652-4
172.
AzmitiaECRubinsteinVJStrafaciJARiosJCWhitaker-AzmitiaPM. 5-HT1A agonist and dexamethasone reversal of para-chloroamphetamine induced loss of MAP-2 and synaptophysin immunoreactivity in adult rat brain. Brain Res. (1995) 677:181–92. 10.1016/0006-8993(95)00051-Q
173.
SikichLHickokJMToddRD. 5-HT1A receptors control neurite branching during development. Brain Res Dev Brain Res. (1990) 56:269–74. 10.1016/0165-3806(90)90092-D
174.
RojasPSNeiraDMunozMLavanderoSFiedlerJL. Serotonin (5-HT) regulates neurite outgrowth through 5-HT1A and 5-HT7 receptors in cultured hippocampal neurons. J Neurosci Res. (2014) 92:1000–9. 10.1002/jnr.23390
175.
RumajogeePVergeDHanounNBrisorgueilMJHenRLeschKPet al. Adaptation of the serotoninergic neuronal phenotype in the absence of 5-HT autoreceptors or the 5-HT transporter: involvement of BDNF and cAMP. Eur J Neurosci. (2004) 19:937–44. 10.1111/j.0953-816X.2004.03194.x
176.
DudokJJGroffenAJWitterMPVoornPVerhageM. Chronic activation of the 5-HT(2) receptor reduces 5-HT neurite density as studied in organotypic slice cultures. Brain Res. (2009) 1302:1–9. 10.1016/j.brainres.2009.08.071
177.
RojasPSFiedlerJL. What do we really know about 5-HT1A receptor signaling in neuronal cells?Front Cell Neurosci. (2016) 10:272. 10.3389/fncel.2016.00272
178.
AlbertPRVahid-AnsariF. The 5-HT1A receptor: signaling to behavior. Biochimie. (2019) 161:34–45. 10.1016/j.biochi.2018.10.015
179.
KushwahaNAlbertPR. Coupling of 5-HT1A autoreceptors to inhibition of mitogen-activated protein kinase activation via Gbetagamma subunit signaling. Eur J Neurosci. (2005) 21:721–32. 10.1111/j.1460-9568.2005.03904.x
180.
MoghaAGuarigliaSRDebataPRWenGYBanerjeeP. Serotonin 1A receptor-mediated signaling through ERK and PKCalpha is essential for normal synaptogenesis in neonatal mouse hippocampus. Transl Psychiatry. (2012) 2:e66. 10.1038/tp.2011.58
181.
AlbertPRSajediNLemondeSGhahremaniMH. Constitutive G(i2)-dependent activation of adenylyl cyclase type II by the 5-HT1A receptor. Inhibition by anxiolytic partial agonists. J Biol Chem. (1999) 274:35469–74. 10.1074/jbc.274.50.35469
182.
MehtaMAhmedZFernandoSSCano-SanchezPAdayevTZiemnickaDet al. Plasticity of 5-HT 1A receptor-mediated signaling during early postnatal brain development. J Neurochem. (2007) 101:918–28. 10.1111/j.1471-4159.2007.04448.x
183.
YuenEYJiangQChenPGuZFengJYanZ. Serotonin 5-HT1A receptors regulate NMDA receptor channels through a microtubule-dependent mechanism. J Neurosci. (2005) 25:5488–501. 10.1523/JNEUROSCI.1187-05.2005
184.
RojasPSAguayoFNeiraDTejosMAliagaEMunozJPet al. Dual effect of serotonin on the dendritic growth of cultured hippocampal neurons: Involvement of 5-HT1A and 5-HT7 receptors. Mol Cell Neurosci. (2017) 85:148–61. 10.1016/j.mcn.2017.09.009
185.
GasparPCasesOMaroteauxL. The developmental role of serotonin: news from mouse molecular genetics. Nat Rev Neurosci. (2003) 4:1002–12. 10.1038/nrn1256
186.
LeschKPWaiderJ. Serotonin in the modulation of neural plasticity and networks: implications for neurodevelopmental disorders. Neuron. (2012) 76:175–91. 10.1016/j.neuron.2012.09.013
187.
BonninAToriiMWangLRakicPLevittP. Serotonin modulates the response of embryonic thalamocortical axons to netrin-1. Nat Neurosci. (2007) 10:588–97. 10.1038/nn1896
188.
VetencourtJFSaleAViegiABaroncelliLDe PasqualeRO'LearyOFet al. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science. (2008) 320:385–8. 10.1126/science.1150516
189.
Maya VetencourtJFTiraboschiESpolidoroMCastrenEMaffeiL. Serotonin triggers a transient epigenetic mechanism that reinstates adult visual cortex plasticity in rats. Eur J Neurosci. (2011) 33:49–57. 10.1111/j.1460-9568.2010.07488.x
190.
AlbertPR. Adult neuroplasticity: a new “cure” for major depression?J Psychiatry Neurosci. (2019) 44:147–50. 10.1503/jpn.190072
191.
CastrenEMonteggiaLM. Brain-derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry. (2021) 90:128–36. 10.1016/j.biopsych.2021.05.008
192.
LeysenJE. 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord. (2004) 3:11–26. 10.2174/1568007043482598
193.
PompeianoMPalaciosJMMengodG. Distribution of the serotonin 5-HT2 receptor family mRNAs: comparison between 5-HT2A and 5-HT2C receptors. Brain Res Mol Brain Res. (1994) 23:163–78. 10.1016/0169-328X(94)90223-2
194.
PersicoAMDi PinoGLevittP. Multiple receptors mediate the trophic effects of serotonin on ventroposterior thalamic neurons in vitro. Brain Res. (2006) 1095:17–25. 10.1016/j.brainres.2006.04.006
195.
DooleyAEPappasISParnavelasJG. Serotonin promotes the survival of cortical glutamatergic neurons in vitro. Exp Neurol. (1997) 148:205–14. 10.1006/exnr.1997.6633
196.
ChameauPVan HooftJA. Serotonin 5-HT(3) receptors in the central nervous system. Cell Tissue Res. (2006) 326:573–81. 10.1007/s00441-006-0255-8
197.
EngelMSmidtMPVan HooftJA. The serotonin 5-HT3 receptor: a novel neurodevelopmental target. Front Cell Neurosci. (2013) 7:76. 10.3389/fncel.2013.00076
198.
LottoBUptonLPriceDJGasparP. Serotonin receptor activation enhances neurite outgrowth of thalamic neurones in rodents. Neurosci Lett. (1999) 269:87–90. 10.1016/S0304-3940(99)00422-X
199.
SunHHuXQEmeritMBSchoenebeckJCKimmelCEPeoplesRWet al. Modulation of 5-HT3 receptor desensitization by the light chain of microtubule-associated protein 1B expressed in HEK 293 cells. J Physiol. (2008) 586:751–62. 10.1113/jphysiol.2007.136440
200.
YuYCaoDQXuHYSunMHuangZLYungWHet al. 5-HT3A receptors are required in long-term depression and AMPA receptor internalization. Neuroscience. (2014) 278:105–12. 10.1016/j.neuroscience.2014.07.070
201.
WaeberCSebbenMNieoullonABockaertJDumuisA. Regional distribution and ontogeny of 5-HT4 binding sites in rodent brain. Neuropharmacology. (1994) 33:527–41. 10.1016/0028-3908(94)90084-1
202.
VilaroMTCortesRGeraldCBranchekTAPalaciosJMMengodG. Localization of 5-HT4 receptor mRNA in rat brain by in situ hybridization histochemistry. Brain Res Mol Brain Res. (1996) 43:356–60. 10.1016/S0169-328X(96)00248-3
203.
BonaventurePHallHGommerenWCrasPLangloisXJurzakMet al. Mapping of serotonin 5-HT(4) receptor mRNA and ligand binding sites in the post-mortem human brain. Synapse. (2000) 36:35–46. 10.1002/(SICI)1098-2396(200004)36:1<35::AID-SYN4>3.0.CO;2-Y
204.
PindonAVan HeckeGVan GompelPLesageASLeysenJEJurzakM. Differences in signal transduction of two 5-HT4 receptor splice variants: compound specificity and dual coupling with Galphas- and Galphai/o-proteins. Mol Pharmacol. (2002) 61:85–96. 10.1124/mol.61.1.85
205.
BarthetGFrameryBGavenFPellissierLReiterEClaeysenSet al. 5-hydroxytryptamine 4 receptor activation of the extracellular signal-regulated kinase pathway depends on Src activation but not on G protein or beta-arrestin signaling. Mol Biol Cell. (2007) 18:1979–91. 10.1091/mbc.e06-12-1080
206.
KvachninaELiuGDityatevARennerUDumuisARichterDWet al. 5-HT7 receptor is coupled to G alpha subunits of heterotrimeric G12-protein to regulate gene transcription and neuronal morphology. J Neurosci. (2005) 25:7821–30. 10.1523/JNEUROSCI.1790-05.2005
207.
RestivoLRomanFDumuisABockaertJMarchettiEAmmassari-TeuleM. The promnesic effect of G-protein-coupled 5-HT4 receptors activation is mediated by a potentiation of learning-induced spine growth in the mouse hippocampus. Neuropsychopharmacology. (2008) 33:2427–34. 10.1038/sj.npp.1301644
208.
KozonoNOhtaniAShigaT. Roles of the serotonin 5-HT4 receptor in dendrite formation of the rat hippocampal neurons in vitro. Brain Res. (2017) 1655:114–21. 10.1016/j.brainres.2016.11.021
209.
SchillYBijataMKopachOCherkasVAbdel-GalilDBöhmKet al. Serotonin 5-HT(4) receptor boosts functional maturation of dendritic spines via RhoA-dependent control of F-actin. Commun Biol. (2020) 3:76. 10.1038/s42003-020-0791-x
210.
LecoufletPRouxCMPotierBLegerMBrunetEBillardJMet al. Interplay between 5-HT4 Receptors and GABAergic system within CA1 hippocampal synaptic plasticity. Cereb Cortex. (2021) 31:694–701. 10.1093/cercor/bhaa253
211.
WawraMFidzinskiPHeinemannUModyIBehrJ. 5-HT4-receptors modulate induction of long-term depression but not potentiation at hippocampal output synapses in acute rat brain slices. PLoS One. (2014) 9:e88085. 10.1371/journal.pone.0088085
212.
CavacciniAGrittiMGiorgiALocarnoAHeckNMigliariniSet al. Serotonergic signaling controls input-specific synaptic plasticity at striatal circuits. Neuron. (2018) 98:801–816e807. 10.1016/j.neuron.2018.04.008
213.
HuangYYKandelER. 5-Hydroxytryptamine induces a protein kinase A/mitogen-activated protein kinase-mediated and macromolecular synthesis-dependent late phase of long-term potentiation in the amygdala. J Neurosci. (2007) 27:3111–9. 10.1523/JNEUROSCI.3908-06.2007
214.
KobayashiKIkedaYSakaiAYamasakiNHanedaEMiyakawaTet al. Reversal of hippocampal neuronal maturation by serotonergic antidepressants. Proc Natl Acad Sci U S A. (2010) 107:8434–9. 10.1073/pnas.0912690107
215.
KobayashiKIkedaYSuzukiH. Behavioral destabilization induced by the selective serotonin reuptake inhibitor fluoxetine. Mol Brain. (2011) 4:12. 10.1186/1756-6606-4-12
216.
AmigoJDiazAPilar-CuellarFVidalRMartinACompanVet al. The absence of 5-HT4 receptors modulates depression- and anxiety-like responses and influences the response of fluoxetine in olfactory bulbectomised mice: Adaptive changes in hippocampal neuroplasticity markers and 5-HT1A autoreceptor. Neuropharmacology. (2016) 111:47–58. 10.1016/j.neuropharm.2016.08.037
217.
SamuelsBAMendez-DavidIFayeCDavidSAPierzKAGardierAMet al. Serotonin 1A and serotonin 4 receptors: essential mediators of the neurogenic and behavioral actions of antidepressants. Neuroscientist. (2016) 22:26–45. 10.1177/1073858414561303
218.
LucasGRymarVVDuJMnie-FilaliOBisgaardCMantaSet al. Serotonin(4) (5-HT(4)) receptor agonists are putative antidepressants with a rapid onset of action. Neuron. (2007) 55:712–25. 10.1016/j.neuron.2007.07.041
219.
WardRPHamblinMWLachowiczJEHoffmanBJSibleyDRDorsaDM. Localization of serotonin subtype 6 receptor messenger RNA in the rat brain by in situ hybridization histochemistry. Neuroscience. (1995) 64:1105–11. 10.1016/0306-4522(94)00439-C
220.
GerardCMartresMPLefèvreKMiquelMCVergéDLanfumeyLet al. Immuno-localization of serotonin 5-HT6 receptor-like material in the rat central nervous system. Brain Res. (1997) 746:207–19. 10.1016/S0006-8993(96)01224-3
221.
RobertsJCReavillCEastSZHarrisonPJPatelSRoutledgeCet al. The distribution of 5-HT6 receptors in rat brain: an autoradiographic binding study using the radiolabelled 5-HT6 receptor antagonist [125I]SB-258585. Brain Res. (2002) 934:49–57. 10.1016/S0006-8993(02)02360-0
222.
KingMVMarsdenCAFoneKC. A role for the 5-HT(1A), 5-HT4 and 5-HT6 receptors in learning and memory. Trends Pharmacol Sci. (2008) 29:482–92. 10.1016/j.tips.2008.07.001
223.
Monsma FJJrShenYWardRPHamblinMWSibleyDR. Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs. Mol Pharmacol. (1993) 43:320–7.
224.
YunHMKimSKimHJKostenisEKimJISeongJYet al. The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn. J Biol Chem. (2007) 282:5496–505. 10.1074/jbc.M606215200
225.
RiccioniTBordiFMinettiPSpadoniGYunHMImBHet al. ST1936 stimulates cAMP, Ca2+, ERK1/2 and Fyn kinase through a full activation of cloned human 5-HT6 receptors. Eur J Pharmacol. (2011) 661:8–14. 10.1016/j.ejphar.2011.04.028
226.
YunHMBaikJHKangIJinCRhimH. Physical interaction of Jab1 with human serotonin 6 G-protein-coupled receptor and their possible roles in cell survival. J Biol Chem. (2010) 285:10016–29. 10.1074/jbc.M109.068759
227.
GuadianaSMSemple-RowlandSDaroszewskiDMadorskyIBreunigJJMykytynKet al. Arborization of dendrites by developing neocortical neurons is dependent on primary cilia and type 3 adenylyl cyclase. J Neurosci. (2013) 33:2626. 10.1523/JNEUROSCI.2906-12.2013
228.
LesiakAJBrodskyMCohencaNCroicuAGNeumaierJF. Restoration of physiological expression of 5-HT(6) receptor into the primary cilia of null mutant neurons lengthens both primary cilia and dendrites. Mol Pharmacol. (2018) 94:731–42. 10.1124/mol.117.111583
229.
DuhrFDélérisPRaynaudFSévenoMMorisset-LopezSMannoury La CourCet al. Cdk5 induces constitutive activation of 5-HT6 receptors to promote neurite growth. Nat Chem Biol. (2014) 10:590–7. 10.1038/nchembio.1547
230.
Chaumont-DubelSDupuyVBockaertJBecamelCMarinP. The 5-HT6 receptor interactome: New insight in receptor signaling and its impact on brain physiology and pathologies. Neuropharmacology. (2020) 172:107839. 10.1016/j.neuropharm.2019.107839
231.
RiccioOPotterGWalzerCValletPSzaboGVutskitsLet al. Excess of serotonin affects embryonic interneuron migration through activation of the serotonin receptor 6. Mol Psychiatry. (2009) 14:280–90. 10.1038/mp.2008.89
232.
JacobshagenMNiquilleMChaumont-DubelSMarinPDayerA. The serotonin 6 receptor controls neuronal migration during corticogenesis via a ligand-independent Cdk5-dependent mechanism. Development. (2014) 141:3370–7. 10.1242/dev.108043
233.
SunZWangBChenCLiCZhangY. 5-HT6R null mutatrion induces synaptic and cognitive defects. Aging Cell. (2021) 20:e13369. 10.1111/acel.13369
234.
De FoubertGO'neillMJZetterstromTS. Acute onset by 5-HT(6)-receptor activation on rat brain brain-derived neurotrophic factor and activity-regulated cytoskeletal-associated protein mRNA expression. Neuroscience. (2007) 147:778–85. 10.1016/j.neuroscience.2007.04.045
235.
DawsonLANguyenHQLiP. The 5-HT(6) receptor antagonist SB-271046 selectively enhances excitatory neurotransmission in the rat frontal cortex and hippocampus. Neuropsychopharmacology. (2001) 25:662–8. 10.1016/S0893-133X(01)00265-2
236.
WestPJMarcyVRMarinoMJSchaffhauserH. Activation of the 5-HT(6) receptor attenuates long-term potentiation and facilitates GABAergic neurotransmission in rat hippocampus. Neuroscience. (2009) 164:692–701. 10.1016/j.neuroscience.2009.07.061
237.
MeffreJChaumont-DubelSMannoury La CourCLoiseauFWatsonDJDekeyneAet al. 5-HT(6) receptor recruitment of mTOR as a mechanism for perturbed cognition in schizophrenia. EMBO Mol Med. (2012) 4:1043–56. 10.1002/emmm.201201410
238.
WesołowskaANikiforukA. Effects of the brain-penetrant and selective 5-HT6 receptor antagonist SB-399885 in animal models of anxiety and depression. Neuropharmacology. (2007) 52:1274–83. 10.1016/j.neuropharm.2007.01.007
239.
SmithGSBarrettFSJooJHNasseryNSavonenkoASodumsDJet al. Molecular imaging of serotonin degeneration in mild cognitive impairment. Neurobiol Dis. (2017) 105:33–41. 10.1016/j.nbd.2017.05.007
240.
HedlundPBSutcliffeJG. Functional, molecular and pharmacological advances in 5-HT7 receptor research. Trends Pharmacol Sci. (2004) 25:481–6. 10.1016/j.tips.2004.07.002
241.
HedlundPBHuitron-ResendizSHenriksenSJSutcliffeJG. 5-HT7 receptor inhibition and inactivation induce antidepressantlike behavior and sleep pattern. Biol Psychiatry. (2005) 58:831–7. 10.1016/j.biopsych.2005.05.012
242.
BlattnerKMCanneyDJPippinDABlassBE. Pharmacology and therapeutic potential of the 5-HT(7) receptor. ACS Chem Neurosci. (2019) 10:89–119. 10.1021/acschemneuro.8b00283
243.
ShenYMonsmaFJJrMetcalfMAJosePAHamblinMWSibleyDR. Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype. J Biol Chem. (1993) 268:18200–4. 10.1016/S0021-9258(17)46830-X
244.
GustafsonELDurkinMMBardJAZgombickJBranchekTA. A receptor autoradiographic and in situ hybridization analysis of the distribution of the 5-ht7 receptor in rat brain. Br J Pharmacol. (1996) 117:657–66. 10.1111/j.1476-5381.1996.tb15241.x
245.
AdhamNZgombickJMBardJBranchekTA. Functional characterization of the recombinant human 5-hydroxytryptamine7(a) receptor isoform coupled to adenylate cyclase stimulation. J Pharmacol Exp Ther. (1998) 287:508–14.
246.
SchererSLCainMDKanaiSMKaltenbronnKMBlumerKJ. Regulation of neurite morphogenesis by interaction between R7 regulator of G protein signaling complexes and G protein subunit Gα(13). J Biol Chem. (2017) 292:9906–18. 10.1074/jbc.M116.771923
247.
KatohHAokiJYamaguchiYKitanoYIchikawaANegishiM. Constitutively active Galpha12, Galpha13, and Galphaq induce Rho-dependent neurite retraction through different signaling pathways. J Biol Chem. (1998) 273:28700–7. 10.1074/jbc.273.44.28700
248.
NürnbergABraüerAUWettschureckNOffermannsS. Antagonistic regulation of neurite morphology through Gq/G11 and G12/G13. J Biol Chem. (2008) 283:35526–31. 10.1074/jbc.M804972200
249.
HolstKGusevaDSchindlerSSixtMBraunAChopraHet al. The serotonin receptor 5-HT7R regulates the morphology and migratory properties of dendritic cells. J Cell Sci. (2015) 128:2866–80. 10.1242/jcs.167999
250.
SperanzaLGiulianoTVolpicelliFDe StefanoMELombardiLChamberyAet al. Activation of 5-HT7 receptor stimulates neurite elongation through mTOR, Cdc42 and actin filaments dynamics. Front Behav Neurosci. (2015) 9:62. 10.3389/fnbeh.2015.00062
251.
BijataMLabusJGusevaDStawarskiMButzlaffMDzwonekJet al. Synaptic remodeling depends on signaling between serotonin receptors and the extracellular matrix. Cell Rep. (2017) 19:1767–82. 10.1016/j.celrep.2017.05.023
252.
SperanzaLLabusJVolpicelliFGusevaDLacivitaELeopoldoMet al. Serotonin 5-HT7 receptor increases the density of dendritic spines and facilitates synaptogenesis in forebrain neurons. J Neurochem. (2017) 141:647–61. 10.1111/jnc.13962
253.
OlusakinJMoutkineIDumasSPonimaskinEPaizanisESoiza-ReillyMet al. Implication of 5-HT7 receptor in prefrontal circuit assembly and detrimental emotional effects of SSRIs during development. Neuropsychopharmacology. (2020) 45:2267–77. 10.1038/s41386-020-0775-z
254.
SandvigIAugestadILHåbergAKSandvigA. Neuroplasticity in stroke recovery. The role of microglia in engaging and modifying synapses and networks. Eur J Neurosci. (2018) 47:1414–28. 10.1111/ejn.13959
255.
PatelYParkerNShinJHowardDFrenchLThomopoulosSIet al. Virtual histology of cortical thickness and shared neurobiology in 6 psychiatric disorders. JAMA Psychiatry. (2021) 78:47–63. 10.1001/jamapsychiatry.2020.2694
256.
Vahid-AnsariFAlbertPR. chronic fluoxetine induces activity changes in recovery from poststroke anxiety, depression, and cognitive impairment. Neurotherapeutics. (2018) 15:200–15. 10.1007/s13311-017-0590-3
257.
UnderwoodMDKassirSABakalianMJGalfalvyHMannJJArangoV. Neuron density and serotonin receptor binding in prefrontal cortex in suicide. Int J Neuropsychopharmacol. (2012) 15:435–47. 10.1017/S1461145711000691
258.
UnderwoodMDKassirSABakalianMJGalfalvyHDworkAJMannJJet al. Serotonin receptors and suicide, major depression, alcohol use disorder and reported early life adversity. Transl Psychiatry. (2018) 8:279. 10.1038/s41398-018-0309-1
259.
RollsETChengWFengJ. The orbitofrontal cortex: reward, emotion and depression. Brain Commun. (2020) 2:fcaa196. 10.1093/braincomms/fcaa196
260.
DrevetsWC. Orbitofrontal cortex function and structure in depression. Ann N Y Acad Sci. (2007) 1121:499–527. 10.1196/annals.1401.029
261.
HahnAHaeuslerDKrausCHoflichASKranzGSBaldingerPet al. Attenuated serotonin transporter association between dorsal raphe and ventral striatum in major depression. Hum Brain Mapp. (2014) 35:3857–66. 10.1002/hbm.22442
262.
BhagwagarZMurthyNSelvarajSHinzRTaylorMFancySet al. 5-HTT binding in recovered depressed patients and healthy volunteers: a positron emission tomography study with [11C]DASB. Am J Psychiatry. (2007) 164:1858–65. 10.1176/appi.ajp.2007.06111933
263.
MeyerJHHouleSSagratiSCarellaAHusseyDFGinovartNet al. Brain serotonin transporter binding potential measured with carbon 11-labeled DASB positron emission tomography: effects of major depressive episodes and severity of dysfunctional attitudes. Arch Gen Psychiatry. (2004) 61:1271–9. 10.1001/archpsyc.61.12.1271
264.
LanzenbergerRKranzGSHaeuslerDAkimovaESavliMHahnAet al. Prediction of SSRI treatment response in major depression based on serotonin transporter interplay between median raphe nucleus and projection areas. Neuroimage. (2012) 63:874–81. 10.1016/j.neuroimage.2012.07.023
265.
AnanthMBartlettEADelorenzoCLinXKunkelLVadhanNPet al. Prediction of lithium treatment response in bipolar depression using 5-HTT and 5-HT1A PET. Eur J Nucl Med Mol Imaging. (2020) 47:2417–28. 10.1007/s00259-020-04681-6
266.
BeliveauVSvarerCFrokjaerVGKnudsenGMGreveDNFisherPM. Functional connectivity of the dorsal and median raphe nuclei at rest. Neuroimage. (2015) 116:187–95. 10.1016/j.neuroimage.2015.04.065
267.
WeinsteinJJRogersBPTaylorWDBoydBDCowanRLSheltonKMet al. Effects of acute tryptophan depletion on raphe functional connectivity in depression. Psychiatry Res. (2015) 234:164–71. 10.1016/j.pscychresns.2015.08.015
Summary
Keywords
serotonin, neuroplasticity, antidepressant (AD), serotonin receptors, axonal guidance and plasticity
Citation
Vahid-Ansari F and Albert PR (2021) Rewiring of the Serotonin System in Major Depression. Front. Psychiatry 12:802581. doi: 10.3389/fpsyt.2021.802581
Received
26 October 2021
Accepted
17 November 2021
Published
16 December 2021
Volume
12 - 2021
Edited by
Reza Rahimian, McGill University, Canada
Reviewed by
Luc Maroteaux, INSERM U839 Institut du Fer à Moulin (IFM), France; Bruno Pierre Guiard, Université de Toulouse, France
Updates
Copyright
© 2021 Vahid-Ansari and Albert.
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: Paul R. Albert palbert@uottawa.ca
This article was submitted to Molecular Psychiatry, a section of the journal Frontiers in Psychiatry
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.