Synaptic SNAREs in neurotransmission and neurodevelopmental disorders

Synaptic SNARE proteins—syntaxin, SNAP-25, and VAMP/synaptobrevin—are essential for vesicle docking and fusion at the presynaptic terminal, governing the precision of neurotransmitter release. Disruption of this machinery is increasingly recognized as a driver of altered synaptic function and plasticity in autism spectrum disorder and other neurodevelopmental conditions. Genetic studies have identified rare SNARE-related variants in individuals with autism spectrum disorder (ASD), epileptic encephalopathies, intellectual disability, and schizophrenia, drawing attention to the central role of SNARE dysfunction in the etiology of these disorders. SNARE dysfunction disrupts excitatory/inhibitory balance, local translation, and network synchrony, leading to the core behavioral phenotypes of neurodevelopmental disorders. Furthermore, interactions between SNAREs and other synaptic proteins such as neuroligins, neurexins, and SHANKs highlight their centrality to the “synaptopathy” model of autism spectrum disorder and related conditions.Recent research has further uncovered SNAREs' involvement in major neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Huntington’s, and ALS, suggesting that SNARE dysfunction bridges early developmental perturbations and late-onset degeneration. While molecular and genetic studies have illuminated new mechanisms of SNARE regulation and highlighted pathogenic variants, several gaps remain. These include a more comprehensive understanding of SNARE structure-function relationships, the regulatory roles of Munc18, complexin, synaptotagmin, Ca²⁺ signaling, and the consequences of post-translational modifications. Advances in animal and iPSC-derived neuronal models are revealing how SNARE dysfunction manifests at cellular and systems levels, but the translation of these insights to effective intervention is still at an early stage. Ongoing debates and research are also focused on the broader roles of SNARE-mediated gliotransmission and contribution to network-level dysfunction.This Research Topic aims to bring together experts across molecular neuroscience, genetics, and clinical translation to explore how synaptic SNARE biology bridges basic mechanisms with disease pathogenesis. The main objectives are to integrate perspectives on molecular and synaptic mechanisms, decipher the impact of SNARE gene variants on neurodevelopment and disease, and accelerate the development of therapeutic and technological advances targeting SNARE pathways. By uniting original contributions and reviews from diverse fields, this topic seeks to advance our understanding of how SNAREs underpin both health and disease, offering insights into strategies for intervention in neurodevelopmental and neurodegenerative disorders.To gather further insights into synaptic SNARE biology in neurodevelopmental and neurodegenerative disorders, we welcome articles that span basic molecular research to translational applications. We invite submissions of original research articles, reviews, mini-reviews, and perspective & opinion that address, but are not limited to, the following themes:o SNARE structure–function relationships in synaptic vesicle fusiono Regulation by Munc18, complexin, synaptotagmin, and Ca²⁺ signalingo Post-translational modifications and lipid environment effectso SNARE gene variants linked to ASD, epilepsy, and intellectual disabilityo SNARE dysfunction and excitatory/inhibitory imbalance in developing circuitso Interactions of SNAREs with synaptic scaffolding proteins in neurodevelopmental disease pathogenesiso Animal and iPSC-derived neuronal models of SNARE-related neurodevelopmental disorders (NDDs)o SNAREs in Alzheimer’s, Parkinson’s, Huntington’s, and ALSo Crosstalk between SNARE dysfunction in early developmental vs. late degenerative diseaseo SNARE-mediated gliotransmission and circuit synchrony in network dysfunctiono Therapeutic strategies targeting SNARE pathways, including RNA, gene therapy, and pharmacological approacheso Advances in cryo-EM, live imaging, and single-synapse physiology Topic editors: Paul Carney, Huan Bao, Jie Yang Source: https://www.frontiersin.org/research-topics/73854/synaptic-snares-in-neurotransmission-and-neurodevelopmental-disorders