Synaptosome proteomics of tetanus neurotoxin-injected mice

Network hyperexcitability is manifested as frequent ictal discharges, often caused by unbalanced neurotransmission. We assessed synaptic changes in the hyperexcitable visual cortex of tetanus neurotoxin-injected mice (TeNT). A proteomics analysis of synaptic content revealed Carboxypeptidase E (CPE) up-regulation following TeNT injection. To quantify CPE effect on vesicle clustering, we used an ultrastructural measure of synaptic activity to investigate functional differences at excitatory and inhibitory synapses. We found homeostatic changes in hyperexcitable networks expressed as an early onset lengthening of active zones at inhibitory synapses followed by spatial reorganization at excitatory synapses. Moreover, inhibition of CPE decreases ictal discharges in vivo. This study reveals a complex landscape of homeostatic changes affecting the synaptic release machinery , differentially at inhibitory and excitatory terminals. We propose a novel homeostatic presynaptic mechanism which may impact release timing rather than synaptic strength.