Synaptic Vesicles Dynamics in Neocortical Epilepsy

Neuronal hyperexcitability often results from an unbalance between excitatory and inhibitory neurotransmission, but the synaptic alterations leading to enhanced seizure propensity are only partly understood. Here we assess changes in functional synaptic pools in mouse visual cortex made epileptic by tetanus neurotoxin (TeNT) injection. Using an ultrastructural measure of synaptic activity, we quantified functional differences at excitatory and inhibitory synapses. We found homeostatic changes in epileptic networks, expressed as an early onset lengthening of active zones at inhibitory synapses, followed by spatial reorganization of recycled vesicles at excitatory synapses. A proteomic analysis of synaptic content revealed an upregulation of Carboxypeptidase E (CPE) following TeNT injection; remarkably, its inhibition rapidly decreased network discharges in vivo. Altogether, our analyses reveal a complex landscape of changes affecting the epileptic synaptic release machinery, unveiling presynaptic mechanisms which may impact vesicles’ release timing rather than synaptic strength. Our results indicate i) altered positioning of release-competent vesicles as a novel signature of epileptic networks and ii) inhibiting CPE a potential therapeutic strategy to counteract epileptic discharges.