Synaptic vesicle (SV) cycle is the fundamental and tightly regulated process that allows neuron communication in the brain. SV cycling takes place at both inhibitory and excitatory synapses, but little is known on the differences in SV trafficking mechanisms between them, although GABAergic and glutamatergic synapses differ both morphologically and functionally.

We here describe the role of Synapsins (Syns), a family of SV-associated phosphoproteins, in the regulation of SV pools at excitatory and inhibitory synapses and describe the impact on synaptic function of a Syn1 nonsense mutation (SynID555) described in a human family segregating epilepsy and autism.

We performed morphometric analysis, live imaging experiments and patch-clamp recordings from SynI knockout neurons expressing either WT-SynI or SynID555. Our results revealed a central role of Syns in the regulation of SV pool dynamics at both inhibitory and excitatory synapses, and distinct defects of the mutation in the two synaptic subtypes. Reserve pool of SV and synchronous release were impaired at GABAergic synapses, whereas release probability, paired-pulse facilitation and post-tetanic potentiation were affected at glutamatergic synapses. The resulting excitation/inhibition imbalance led to network hyperexcitability, as assessed by multielectrode array recordings, which is likely to trigger epileptogenesis in patients carrying the mutation.