Levetiracetam inhibits endocytosis and augments short-term depression

Levetiracetam (LEV) is an anti-epileptic drug with demonstrated efficacy against generalized seizures. Recent studies have found that LEV affects the release of neurotransmitters by binding to synaptic vesicle protein 2A (SV2A). However, the details of LEV regulation of synaptic transmission remain poorly understood. Here, we used the whole-cell patch-clamp technique to further characterize the effects of LEV on synaptic transmission at a large mammalian central synapse, the calyx of Held. Our results showed that two common forms of vesicle endocytosis, including slow and rapid endocytosis, were dramatically inhibited when slices were incubated in 100 μM LEV for 1 h, however, the action potential (AP), calcium influx and exocytosis were not affected. Furthermore, by measuring the level of steady-state depression induced by 100 Hz stimulus trains, we found that the steady state level of depression was significantly stronger after LEV treatment, indicating that LEV enhanced short-term depression (STD). Thus, these findings suggested that the mechanisms of the antiepileptic of LEV seem to be mediated, at least partly, by regulating endocytosis and STD.