Role of somatic HCN in epileptiform activity in subicular neurons

Abstract

ABSTRACTThe subiculum, owing to its bursting nature and recurrent connections, plays a critical role in Temporal Lobe Epilepsy (TLE). Studying neuronal subtypes in the subiculum can elucidate the mechanisms underlying the patterning of epileptiform firing. We observed that epileptogenic 4AP-0Mg induced different patterns of epileptiform discharges in burst firing neurons and interneurons. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate the intrinsic excitability of the neurons by governing the neuronal firing properties and membrane potential. To study the role of Ih(HCN currents) in epileptiform activity in subicular neurons, we modeled subicular HCN currents in the dynamic clamp that mimicked downregulation and overexpression observed in epilepsy-associated pathophysiology. Our results indicated that the burst firing neurons contribute to the epileptic firing characteristics due to HCN in the subiculum. We subsequently investigated the homeostatic modulation of HCN during the epileptiform activity in subicular burster cells. Our study is the first report showing Ihin rat subicular neurons during 4AP 0Mg-induced epileptogenic activity undergoes modulation on a time scale of a few minutes. Additionally, we observed that the changes in sag and chirp responses were persistent after the wash-out of 4AP-0Mg; thus, the changes appear irreversible. Our studies further showed that the neuronal excitability changes paralleled the changes in the HCN conductance during epileptogenesis. We conclude that a very rapid decline in somatic HCN function during epileptiform activity represents a previously unidentified mechanism of homeostatic dysfunction over a very short period, impeding the neuron’s ability to reestablish its regulatory processes in the subicular burster cells.