Epileptogenic Q555X SYN1 mutant triggers imbalances in release dynamics and short-term plasticity.

Mutations in the Synapsin I (SynI) gene are linked to idiopathic epilepsy and autism. SynI is a synaptic vesicle (SV) phosphoprotein playing multiple roles in synaptic transmission and plasticity. We investigated synaptic transmission in hippocampal SynI knockout neurons expressing the recently identified Q555X mutation. Both inhibitory and excitatory neurons displayed impaired basal evoked synchronous release caused by a decrease in the readily-releasable pool in inhibitory synapses and in the release probability in excitatory synapses. Q555X-hSynI induced larger facilitation and post-tetanic potentiation in excitatory synapses and stronger depression after long trains in inhibitory synapses, together with an increase in asynchronous release that was more intense in excitatory synapses. These synaptic changes were associated with higher network excitability and firing/bursting activity. Our data indicate that imbalances in short-term plasticity and release dynamics, but not in basal transmission, of inhibitory and excitatory transmission can trigger network hyperexcitability and lead to epilepsy/autism manifestations.