Synaptic and extrasynaptic origin of the excitation/inhibition imbalance in the hippocampus of synapsin I/II/III knockout mice.

Synapsins (SynI, SynII, SynIII) are a multigene family of synaptic vesicle phosphoproteins implicated in the regulation of synaptic transmission and plasticity. SYN1/2 genes have been identified as major epilepsy susceptibility genes in humans and synapsin I/II/III triple knockout (TKO) mice are epileptic. However, excitatory and inhibitory synaptic transmission and short-term plasticity have never been analyzed in intact neuronal circuits of TKO mice. To clarify the generation and expression of the epileptic phenotype, we performed patch-clamp recordings in the CA1 region of acute hippocampal slices from 1-month-old pre-symptomatic and 6-months-old epileptic TKO mice and age-matched controls. We found a strong imbalance between basal glutamatergic and GABAergic transmission with increased eEPSC and impaired eIPSC amplitude. This imbalance was accompanied by a parallel derangement of short-term plasticity paradigms, with enhanced facilitation of glutamatergic transmission in the pre-symptomatic phase and milder depression of inhibitory synapses in the symptomatic phase. Interestingly, a lower tonic GABAA current due to the impaired GABA release is responsible for the more depolarized resting potential found in TKO CA1 neurons, which makes them more susceptible to fire. All these changes preceded the appearance of epilepsy, indicating that the distinct changes in excitatory and inhibitory transmission due to the absence of Syns initiate the epileptogenic process.