Activity-dependent LTP in the dentate gyrus promotes epileptic seizures

Abstract

Epilepsy is a devastating brain disorder whose cellular mechanisms remain poorly understood. Excitatory mossy cells (MCs) in the dentate gyrus of the hippocampus are implicated in temporal lobe epilepsy, the most common form of focal epilepsy in adults. However, the role of MCs during initial seizures, before MC loss occurs, is unclear. Here, we show that initial seizures induced with kainic acid (KA) intraperitoneal injection in adult mice, a well-established model of experimental epilepsy, not only increased MC and granule cell (GC) activity in vivo, but also triggered a BDNF-dependent long-term potentiation at MC-GC synapses (MC-GC LTP). In vivo induction of MC-GC LTP worsened KA-induced seizures, whereas selective MC silencing and Bdnf genetic removal from GCs, which abolishes LTP, were both anti-epileptic. Thus, initial seizures strengthen MC-GC synaptic transmission, thereby promoting epileptic activity. Our findings reveal a potential mechanism of epileptogenesis that may help develop therapeutic strategies for early intervention.