Role of HCN Currents in Epileptiform Activity in Subicular Neurons

Abstract

Subicular neurons play a critical role in Temporal Lobe Epilepsy. While studies have shed light on how synaptic conductances contribute to epileptiform activity in these neurons, it is still unclear how intrinsic conductances influence epileptic discharges. HCN channels play crucial role in pathophysiology by modulating the electrophysiological properties of neurons. To investigate the ability of intrinsic properties in a subicular neuron to generate epileptiform activity, we studied the effects of Ih (HCN) currents in 4‐Aminopyridine magnesium‐free epileptic model in various classes of subicular neurons. To study the modulation of epileptiform activity due to Ih in these neurons, we modeled subicular HCN currents in dynamic clamp that mimicked the effects of blocker and overexpression. We observed similar changes in input resistances with the subtraction and addition of currents in burst firing, regular firing and interneurons. However, the firing rate characteristics during epileptiform activity with the modulation of HCN channels in burst firing and regular firing differed from those observed in interneurons. The results indicated that the burster cells majorly contribute to the epileptic firing characteristics due to HCN in subiculum.During the epileptiform activity, these bursters showed progressive loss of homeostatic compensation characterized by decrease in sag ratio and and loss in theta frequency. The loss of homeostatic compensation incurred was found to be irreversible. These irreversible changes are also characterized by altered HCN channel kinetics. To study how these epilepsy‐induced alterations govern neuronal excitability, we studied the electrophysiological profiles of subicular neurons with altered HCN current kinetics introduced through dynamic clamp in the presence of ZD7288. These irreversible changes are also characterized by altered HCN channel kinetics. To study how these epilepsy‐induced alterations govern neuronal excitability, we studied the electrophysiological profiles of subicular neurons with altered HCN current kinetics introduced through dynamic clamp in the presence of ZD7288. The results showed that the theta selectivity and sag profiles were modulated and post‐inhibitory rebound firing were evoked making the cell hyperexcitable. It is known that the stable neuronal network is homeostatically regulated by intrinsic excitability and synaptic currents. Studies are being conducted to understand the interaction between Ih and synaptic currents before and during the epileptiform activity in neurons with post‐epileptic induced hyperexcitability.