Abstracts

Rationale: Epilepsy is a devastating brain disorder whose cellular mechanisms remain poorly understood. Mossy cells (MCs), excitatory neurons in the dentate gyrus of the hippocampus, are critically involved in temporal lobe epilepsy, the most common form of focal epilepsy in adults. However, the role of MCs during initial seizures, before massive MC loss occurs, is not fully understood. Recurrent excitatory activity is a core mechanism in epilepsy. In the DG, glutamatergic MCs and granule cells (GCs) are reciprocally connected thus forming an intrinsic excitatory loop. Remarkably, a single MC makes more than 30,000 synaptic contact onto GCs, locally, contralaterally, and along the longitudinal axis of the hippocampus. It is therefore conceivable that activity-dependent strengthening of MC output could promote epilepsy through their extensive projections onto GCs. While an episode of prolonged seizures (e.g. status epilepticus) can result in TLE, it is unknown whether and how initial seizures can impact MC-GC synaptic strength.

Methods: Here we used multiple complementary approaches, such as chemogenetics, in vitro electrophysiology, in vivo optogenetics, in vivo calcium imaging, and a conditional knockout strategy.

Results: We showed that initial seizures induced with kainic acid (KA) intraperitoneal injection in adult mice, a well-established model of epilepsy, increased MC and granule cell (GC) activity in vivo, and 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.

Conclusions: 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.

Funding: Please list any funding that was received in support of this abstract.: National Institute of Health (NIH), R01-NS113600 and R01-MH125772R01 grants DA017392, MH081935 to PEC. Fondation pour la Recherche Médicale (Postdoctoral Fellowship for a research abroad), the Fondation Bettencourt Schueller (Prix pour les Jeunes Chercheurs 2016) and the American Epilepsy Society Postdoctoral Research Fellowship (2020) to KN. R21-MH120496 to YY.