Neuronal networks' hyperexcitability often results from an unbalance between excitatory and inhibitory neurotransmission; however, underlying synaptic alterations leading to this condition remain poorly understood. Here, we assess synaptic changes in the visual cortex of epileptic tetanus neurotoxin-injected mice. Using an ultrastructural measure of synaptic activity, we quantified functional differences at excitatory and inhibitory synapses. We found homeostatic changes in hyperexcitable

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... ks, 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 tetanus neurotoxin (TeNT) injection. Remarkably, inhibition of CPE rapidly decreased network discharges in vivo. These analyses reveal a complex landscape of homeostatic changes affecting the epileptic synaptic release machinery, differentially at inhibitory and excitatory terminals. Our study unveil homeostatic presynaptic mechanisms which may impact release timing rather than synaptic strength.