Decoding Presynaptic Function: Molecular Insights into Vesicle Docking, Priming, and Neurotransmitter Release

Recent advances in structural biology, super-resolution microscopy, and quantitative proteomics have transformed our understanding of the presynaptic terminal, revealing an extraordinary level of molecular organisation that underpins the speed, precision, and plasticity of neurotransmitter release. At the centre of this machinery lies the active zone, a nanoscale protein scaffold assembled from core components including RIM, ELKS/CAST, Munc13, RIM-BP, Bassoon, and Piccolo, which positions synaptic vesicles at defined release sites and couples them to voltage-gated calcium channels with nanometre-scale precision. The SNARE complex, formed by Syntaxin-1, SNAP-25, and Synaptobrevin/VAMP2, drives membrane fusion, with the calcium sensor Synaptotagmin and regulatory proteins such as Complexin and Munc18 tuning the kinetics and fidelity of fusion in response to calcium influx. These molecular principles operate across diverse synapse types and developmental stages, and are subject to post-translational modification, activity-dependent regulation, and modulation by presynaptic G-protein coupled receptors and second messenger cascades. The capacity of many neurons to co-package and co-release multiple transmitters, including fast amino acid transmitters, monoamines, and neuropeptides, adds a further layer of complexity to presynaptic organisation, with vesicular transporter expression, vesicle pool segregation, and active zone composition collectively shaping which signals are released, in what proportion, and under what activity conditions.

Perturbations in the molecular machinery governing vesicle docking, priming, and neurotransmitter release have been implicated in a broad spectrum of neurological and psychiatric conditions. Mutations in SNARE complex components, active zone scaffold proteins, and their regulatory partners give rise to synaptopathies associated with epilepsy, intellectual disability, autism spectrum disorder, and childhood-onset neurodevelopmental conditions. Alterations in presynaptic vesicle trafficking and release probability are increasingly recognised as early events in neurodegeneration: in Parkinson’s disease, α-synuclein disrupts SNARE assembly and vesicle recycling, while in Alzheimer’s disease, presynaptic terminal dysfunction precedes frank neuronal loss and correlates with cognitive decline. At the circuit level, short-term synaptic plasticity is governed by the molecular state of the active zone and the size and composition of the readily releasable vesicle pool, and its dysregulation contributes to imbalanced excitation-inhibition and aberrant network dynamics across multiple disease contexts. Disrupted co-transmission is also emerging as a mechanistic feature of neuropsychiatric and neurodegenerative conditions, with altered dopamine-glutamate co-release implicated in addiction and Parkinson’s disease pathophysiology, and dysregulated neuropeptide co-release contributing to disrupted homeostatic and affective circuit function. Understanding the molecular logic of the presynaptic release apparatus, and how its organisation and regulation break down in disease, therefore represents a critical frontier in molecular neuroscience with significant therapeutic implications.

This Research Topic aims to bring together studies that dissect the molecular mechanisms underlying vesicle docking, priming, and neurotransmitter release at the presynaptic terminal, including the molecular basis of co-transmission across diverse neuron types and physiological contexts. By integrating structural, biochemical, cell-biological, and physiological perspectives, this collection seeks to provide a unified framework for understanding how the active zone scaffold, SNARE machinery, and associated regulatory proteins co-operate to achieve fast, reliable, and plastic neurotransmission across synapse types and physiological contexts.

We welcome submissions employing molecular, structural, biochemical, electrophysiological, and imaging approaches, including cryo-electron microscopy and tomography, super-resolution and live-cell imaging, in vitro reconstitution systems, genetically encoded neurotransmitter biosensors, single-cell and spatial transcriptomics, and optogenetic or chemogenetic manipulation of presynaptic function. Studies using in vivo genetic models, iPSC-derived neuronal systems, or patient-derived material to connect presynaptic molecular mechanisms to defined cellular, circuit, or disease-relevant phenotypes are particularly encouraged. Contributions addressing presynaptic function across diverse model organisms, synapse types, and developmental stages are welcome.

Topics of interest include, but are not limited to:

- Molecular architecture and assembly of the active zone scaffold, including the roles of RIM, ELKS/CAST, Munc13, RIM-BP, Bassoon, and Piccolo in organising docking and release sites
- Mechanisms of synaptic vesicle docking, priming, and the regulation of the readily releasable pool and other vesicle pool states
- SNARE complex assembly, disassembly, and conformational dynamics during calcium-triggered membrane fusion
- Calcium sensing by Synaptotagmin isoforms and the contributions of Complexin, Munc18, and other regulatory factors to clamping spontaneous fusion and triggering synchronous release
- Post-translational modifications, including phosphorylation, ubiquitination, and palmitoylation, that regulate presynaptic protein function, active zone composition, and vesicle pool dynamics
- Presynaptic G-protein coupled receptor signalling, second messenger cascades, and activity-dependent modulation of release probability and short-term plasticity
- Molecular bases of short-term synaptic plasticity, including facilitation, depression, augmentation, and post-tetanic potentiation
- Structural insights into presynaptic supramolecular assemblies from cryo-EM, cryo-ET, and integrative structural approaches
- Vesicle trafficking, endocytosis, and recycling pathways that sustain high-fidelity neurotransmitter release during repetitive activity
- Neuronal co-transmission: molecular mechanisms governing vesicular transporter expression, co-packaging of fast transmitters and neuropeptides into shared or segregated vesicle pools, activity-dependent regulation of co-release, and the functional consequences of co-transmission for postsynaptic signalling and circuit computation
- Presynaptic dysfunction in neurological and psychiatric disorders, including synaptopathies, neurodegenerative diseases, epilepsy, and autism spectrum disorders
- Genetic, pharmacological, or optogenetic strategies to restore presynaptic function or compensate for release machinery deficits in disease models