Control of Synaptotagmin-1 Trafficking by SV2A-Mechanism and Consequences for Presynaptic Function and Dysfunction.

Synaptic vesicle protein 2A (SV2A) is an abundant synaptic vesicle cargo with an as yet unconfirmed role in presynaptic function. It is also heavily implicated in epilepsy, firstly being the target of the leading anti-seizure medication levetiracetam and secondly with loss of function mutations culminating in human disease. A range of potential presynaptic functions have been proposed for SV2A; however its interaction with the calcium sensor for synchronous neurotransmitter release, synaptotagmin-1 (Syt1), has received particular attention over the past decade.

Key roles of C2/GAP domains in SYNGAP1-related pathophysiology.

Mutations in SYNGAP1 are a common genetic cause of intellectual disability (ID) and a risk factor for autism. SYNGAP1 encodes a synaptic GTPase-activating protein (GAP) that has both signaling and scaffolding roles. Most pathogenic variants of SYNGAP1 are predicted to result in haploinsufficiency.

SV2A controls the surface nanoclustering and endocytic recruitment of Syt1 during synaptic vesicle recycling.

Following exocytosis, the recapture of plasma membrane-stranded vesicular proteins into recycling synaptic vesicles (SVs) is essential for sustaining neurotransmission. Surface clustering of vesicular proteins has been proposed to act as a 'pre-assembly' mechanism for endocytosis that ensures high-fidelity retrieval of SV cargo. Here, we used single-molecule imaging to examine the nanoclustering of synaptotagmin-1 (Syt1) and synaptic vesicle protein 2A (SV2A) in hippocampal neurons.

Delayed recruitment of activity-dependent bulk endocytosis in Fmr1 knockout neurons.

The presynapse performs an essential role in brain communication via the activity-dependent release of neurotransmitters. However, the sequence of events through which a presynapse acquires functionality is relatively poorly understood, which is surprising, since mutations in genes essential for its operation are heavily implicated in neurodevelopmental disorders. We addressed this gap in knowledge by determining the developmental trajectory of synaptic vesicle (SV) recycling pathways in primary cultures of rat hippocampal neurons.