We are delighted to present the inaugural “Horizons in Synaptic Neuroscience” article collection. This collection showcases high-impact, authoritative and reader-friendly review articles covering the most topical research at the forefront of synaptic neuroscience. All contributing authors were individually nominated by the Chief Editor of the Journal in recognition of their prominence and influence in their respective fields. The cutting-edge work presented in this article collection highlights the diversity of research performed across the entire breadth of the synaptic neuroscience and reflects on the latest advances in the theory, experiment, and methodology with applications to compelling problems in academic and translational research. Contributions to the collection are by invitation only. New articles will be added to this collection as they are published.

McGill University

Uncovering new areas of synaptic neuroscience through exploration of diverse research approaches and topics.

This research topic focuses on the effects of genetic alterations on the transfer of information between neurons, the role of GIPC3 in hereditary deafness, the involvement of astrocytes in synaptic communication, and the association between astrocytes and intellectual disabilities. <ul> <li>Mutations in components of the release machinery can lead to a wide range of psychiatric and neurological symptoms.</li> <li>Screening for variants of GIPC3 is essential for early detection and treatment of deafness.</li> <li>Astrocytes are known to form tripartite synapses and participate in synaptic communication.</li> <li>Neurons that project to the lateral habenula and release both GABA and glutamate have been identified.</li> <li>Astrocytes have been found to play an important role in neural development and in intellectual disabilities.</li> <li>Recent advances in genetic and environmental factors causing intellectual disability and different pharmaceutical effects of intellectual disability-related drugs on astrocytes have been made.</li> </ul>

Frontiers in Synaptic Neuroscience

Horizons in Synaptic Neuroscience

I am delighted to present the inaugural “Horizons in synaptic neuroscience” Research Topic. This Research Topic showcases high-impact, authoritative, and reader-friendly review articles covering the most topical research at the frontiers of synaptic neuroscience. As Chief Editor, I was asked to identify and nominate the contributing authors in recognition of their prominence and influence in their respective fields. The cutting-edge work presented in this Research Topicthus highlights the diversity of research performed across the entire breadth of the synaptic neuroscience field and reflects on the latest advances in primary as well as translational research.In the classic view, synapses are communication devices between neurons. However, together with pre- and postsynaptic neurons, astrocytes form structures called tripartite synapses, by which they participate in bidirectional synaptic communication (<a href="#B5">Perea et al., 2009</a>). Whereas the impact of the transcription factor cyclic adenosine monophosphate (cAMP) response element (CRE)-binding protein (CREB) has been relatively well investigated in neurons, less is known about its role in astrocytes. In their mini review, <a href="https://doi.org/10.3389/fnsyn.2022.1059918">Kim and Kaang</a> therefore explore how CREB mediates responses in astrocytes. They first discuss the classic G protein-coupled receptor activated cAMP/protein kinase A (PKA) pathway for activating CREB, but they also examine non-canonical pathways, such as receptor tyrosine kinases, Notch, and Phosphatidylinositol 3-kinase/Akt. They end with a brief note on CREB in reactive astrocytes and pathology. In sum, this mini review highlights the significance of CREB in gliotransmission from astrocytes to neurons and their synapses, an important but relatively less well studied topic that deserves considerable further research.Another classic view is Dale's law, i.e., the notion that a neuron releases the same chemical transmitter from all its synaptic outputs regardless of target cell identity, a postulate that Sir John Eccles was first to attribute to Henry Dale (<a href="#B2">Eccles et al., 1954</a>). It has, however, long been argued that Dale's principle does not always hold (<a href="#B8">Sossin et al., 1990</a>; <a href="#B3">Jonas et al., 1998</a>; <a href="#B4">Nicoll and Malenka, 1998</a>). The mini review of <a href="https://doi.org/10.3389/fnsyn.2022.1076616">Kim and Sabatini</a> highlights how neurons that release more than one type of neurotransmitter have been found in many organisms and brain areas. They focus more specifically on how a key challenge with exploring synaptic co-transmission lies in the tools and approaches necessary to understand multi-transmitter release. For instance, it can be difficult to determine whether two transmitters are co-packaged in the same vesicles, or alternatively independently released via distinct vesicles of the same presynaptic terminal. Kim and Sabatini discuss the merits of different methods for addressing such queries, such as proteomics, electrophysiology, optical approaches, and statistics.Since neurons critically rely on chemical neurotransmission for information transfer, it is not surprising that malfunction of transmitter release is linked to neuropathology. In their review, <a href="https://doi.org/10.3389/fnsyn.2023.1148957">Uzay and Kavalali</a> discuss how different mutations in various components of the release machinery lead to neurological and psychiatric symptoms, by affecting cross-neuron information transfer and nervous system function. They first explore soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) proteins such as Synaptobrevin-2, SNAP25, and Syntaxin-1, and then move on to investigating the calcium sensor Synaptotagmin-1, the SNARE-stabilizing complexins, the synaptic vesicle fusion protein Munc18-1, and the vesicle priming machinery protein Munc13. The authors conclude that, despite the wealth of knowledge on the synaptic release machinery, there is much to clarify regarding how pathogenic mutations affect release so that we can develop new therapies that are adapted to the distinct dysfunction associated with specific genetic variants.Astrocytes have also been associated with neuropathology, which is perhaps also expected since they vastly outnumber neurons in the brain (<a href="#B7">Sofroniew and Vinters, 2010</a>). In their mini review, <a href="https://doi.org/10.3389/fnsyn.2022.877928">Wang et al.</a> discuss how astrocytes by way of their key role in neurodevelopment have a major impact on diseases related to intellectual disability. They explore reactive astrocytes, ion channel as well as molecular dysfunction, and the role of astrocytes in environmental factors such as excessive alcohol intake during pregnancy. They end by discussing the effects of intellectual disability drugs on astrocytes, to highlight the potential for therapy. One could thus consider the astrocyte both friend and foe in intellectual disability.Globally, &gt;1.5 billion people suffer from hearing loss (<a href="#B1">Chadha et al., 2021</a>). In children, sensorineural hearing loss is the most frequent congenital sensory disorder. Of these cases, 70% have been ascribed to non-syndromic hearing loss (<a href="#B6">Sindura and Banerjee, 2019</a>). In their review, <a href="https://doi.org/10.3389/fnsyn.2022.1101587">Li et al.</a> discuss how the GAIP interacting protein c terminus 3 gene GIPC3 is strongly associated with non-syndromic hearing loss, and how screening for GIPC3 variants is key to early detection of hearing loss in children. They overview the GIPC3 gene, explore effects of GIPC3 mutation on the auditory system, and conclude that focussing on GIPC3 is useful for understanding hereditary deafness and its developmental mechanisms.This Research Topic showcases recent high-profile research at the forefront of synaptic neuroscience. I thank the authors for their hard work and kind contributions, and I hope this Research Topic will inform and inspire future research in the field.PS: Writing&#x2014;original draft, Writing&#x2014;review and editing.The author would like to thank Alanna Watt for help and useful discussions.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.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.

Editorial: Horizons in synaptic neuroscience

Synaptic neurotransmitter release is an evolutionarily conserved process that mediates rapid information transfer between neurons as well as several peripheral tissues. Release of neurotransmitters are ensured by successive events such as synaptic vesicle docking and priming that prepare synaptic vesicles for rapid fusion. These events are orchestrated by interaction of different presynaptic proteins and are regulated by presynaptic calcium. Recent studies have identified various mutations in different components of neurotransmitter release machinery resulting in aberrant neurotransmitter release, which underlie a wide spectrum of psychiatric and neurological symptoms. Here, we review how these genetic alterations in different components of the core neurotransmitter release machinery affect the information transfer between neurons and how aberrant synaptic release affects nervous system function.

Synaptic neurotransmitter release is an evolutionarily conserved process that mediates rapid information transfer between neurons as well as several peripheral tissues. Release of neurotransmitters are ensured by successive events such as synaptic vesicle docking and priming that prepare synaptic vesicles for rapid fusion. These events are orchestrated by interaction of different presynaptic proteins and are regulated by presynaptic calcium. Recent studies have identified various mutations in different components of neurotransmitter release machinery resulting in aberrant neurotransmitter release, which underlie a wide spectrum of psychiatric and neurological symptoms. Here, we review how these genetic alterations in different components of the core neurotransmitter release machinery affect the information transfer between neurons and how aberrant synaptic release affects nervous system function.

Genetic disorders of neurotransmitter release machinery

The GAIP interacting protein c terminus (GIPC) genes encode a small family of proteins characterized by centrally located PDZ domains. GIPC3 encodes a 312 amino acid protein. Variants of human GIPC3 are associated with non-syndromic hearing loss. GIPC3 is one of over a hundred different genes with variants causing human deafness. Screening for variants of GIPC3 is essential for early detection of hearing loss in children and eventually treatment of deafness. Accordingly, this paper assesses the status of research developments on the role of GIPC3 in hereditary deafness and the effects of pathogenic variants on the auditory system.

The GAIP interacting protein c terminus (GIPC) genes encode a small family of proteins characterized by centrally located PDZ domains. GIPC3 encodes a 312 amino acid protein. Variants of human GIPC3 are associated with non-syndromic hearing loss. GIPC3 is one of over a hundred different genes with variants causing human deafness. Screening for variants of GIPC3 is essential for early detection of hearing loss in children and eventually treatment of deafness. Accordingly, this paper assesses the status of research developments on the role of GIPC3 in hereditary deafness and the effects of pathogenic variants on the auditory system.

A review of the mechanisms underlying the role of the GIPC3 gene in hereditary deafness

Astrocytes are known to actively participate in synaptic communication by forming structures called tripartite synapses. These synapses consist of presynaptic axon terminals, postsynaptic dendritic spines, and astrocytic processes where astrocytes release and receive transmitters. Although the transcription factor cyclic AMP response element (CRE)-binding protein (CREB) has been actively studied as an important factor for mediating synaptic activity-induced responses in neurons, its role in astrocytes is relatively unknown. Synaptic signals are known to activate various downstream pathways in astrocytes, which can activate the CREB transcription factor. Therefore, there is a need to summarize studies on astrocytic intracellular pathways that are induced by synaptic communication resulting in activation of the CREB pathway. In this review, we discuss the various neurotransmitter receptors and intracellular pathways that can induce CREB activation and CREB-induced gene regulation in astrocytes.

Astrocytes are known to actively participate in synaptic communication by forming structures called tripartite synapses. These synapses consist of presynaptic axon terminals, postsynaptic dendritic spines, and astrocytic processes where astrocytes release and receive transmitters. Although the transcription factor cyclic AMP response element (CRE)-binding protein (CREB) has been actively studied as an important factor for mediating synaptic activity-induced responses in neurons, its role in astrocytes is relatively unknown. Synaptic signals are known to activate various downstream pathways in astrocytes, which can activate the CREB transcription factor. Therefore, there is a need to summarize studies on astrocytic intracellular pathways that are induced by synaptic communication resulting in activation of the CREB pathway. In this review, we discuss the various neurotransmitter receptors and intracellular pathways that can induce CREB activation and CREB-induced gene regulation in astrocytes.

Cyclic AMP response element-binding protein (CREB) transcription factor in astrocytic synaptic communication

Multi-transmitter neurons, i.e., those that release more than one type of neurotransmitter, have been found in many organisms and brain areas. Given the peculiar biology of these cells, as well as the potential for diverse effects of each of the transmitters released, new tools, and approaches are necessary to parse the mechanisms and functions of synaptic co-transmission. Recently, we and others have studied neurons that project to the lateral habenula and release both gamma-aminobutyric acid (GABA) and glutamate, in some cases by packaging both transmitters in the same synaptic vesicles. Here, we discuss the main challenges with current electrophysiological approaches to studying the mechanisms of glutamate/GABA co-release, a novel statistical analysis that can identify co-packaging of neurotransmitters versus release from separate vesicle, and the implications of glutamate/GABA co-release for synapse function and plasticity.

Multi-transmitter neurons, i.e., those that release more than one type of neurotransmitter, have been found in many organisms and brain areas. Given the peculiar biology of these cells, as well as the potential for diverse effects of each of the transmitters released, new tools, and approaches are necessary to parse the mechanisms and functions of synaptic co-transmission. Recently, we and others have studied neurons that project to the lateral habenula and release both gamma-aminobutyric acid (GABA) and glutamate, in some cases by packaging both transmitters in the same synaptic vesicles. Here, we discuss the main challenges with current electrophysiological approaches to studying the mechanisms of glutamate/GABA co-release, a novel statistical analysis that can identify co-packaging of neurotransmitters versus release from separate vesicle, and the implications of glutamate/GABA co-release for synapse function and plasticity.

Analytical approaches to examine gamma-aminobutyric acid and glutamate vesicular co-packaging

Intellectual disabilities are a type of neurodevelopmental disease caused by neurological dysfunction. Their incidence is largely associated with neural development. Astrocytes are the most widely distributed cells in the mammalian brain. Previous studies have reported that astrocytes only supported and separated the neurons in the brain. However, recent studies have found that they also play an important role in neural development. Understanding the astrocyte mechanism in intellectual development disorder-related diseases will help provide new therapeutic targets for the treatment of intellectual disability-related diseases. This mini-review introduced the association between astrocyte and intellectual disabilities. Furthermore, recent advances in genetic and environmental factors causing intellectual disability and different pharmaceutical effects of intellectual disability-related drugs on astrocytes have been summarised. Finally, we discussed future perspectives of astrocyte-based therapy for intellectual disability.

Intellectual disabilities are a type of neurodevelopmental disease caused by neurological dysfunction. Their incidence is largely associated with neural development. Astrocytes are the most widely distributed cells in the mammalian brain. Previous studies have reported that astrocytes only supported and separated the neurons in the brain. However, recent studies have found that they also play an important role in neural development. Understanding the astrocyte mechanism in intellectual development disorder-related diseases will help provide new therapeutic targets for the treatment of intellectual disability-related diseases. This mini-review introduced the association between astrocyte and intellectual disabilities. Furthermore, recent advances in genetic and environmental factors causing intellectual disability and different pharmaceutical effects of intellectual disability-related drugs on astrocytes have been summarised. Finally, we discussed future perspectives of astrocyte-based therapy for intellectual disability.