Synapsin II Directly Suppresses Epileptic Seizures In Vivo

The synapsin family offers a strong linkage between synaptic mechanisms and the epileptic phenotype. Synapsins are phosphoproteins reversibly associated with synaptic vesicles. Synapsin deficiency can cause epilepsy in humans, and synapsin II (SynII) in knockout (KO) mice causes generalized epileptic seizures. To differentiate between the direct effect of SynII versus its secondary adaptations, we used neonatal intracerebroventricular injections of the adeno-associated virus (AAV) expressing SynII. We found that SynII reintroduction diminished the enhanced synaptic activity in Syn2 KO hippocampal slices. Next, we employed the epileptogenic agent 4-aminopyridine (4-AP) and found that SynII reintroduction completely rescued the epileptiform activity observed in Syn2 KO slices upon 4-AP application. Finally, we developed a protocol to provoke behavioral seizures in young Syn2 KO animals and found that SynII reintroduction balances the behavioral seizures. To elucidate the mechanisms through which SynII suppresses hyperexcitability, we injected the phospho-incompetent version of Syn2 that had the mutated protein kinase A (PKA) phosphorylation site. The introduction of the phospho-incompetent SynII mutant suppressed the epileptiform and seizure activity in Syn2 KO mice, but not to the extent observed upon the reintroduction of native SynII. These findings show that SynII can directly suppress seizure activity and that PKA phosphorylation contributes to this function.