A-type Potassium Channels in Dendritic Integration : Role in Epileptogenesis

Abstract: During cognitive tasks, synchronicity of neural activity varies and is correlated with performance. However, there may be an upper limit to normal synchronised activity – specifically, epileptogenic activity is characterized byexcess spiking at high synchronicity. An epileptic seizure has a complicated course of events and I therefore focused on the synchronised activity preceding a seizure (fast ripples). These high frequency oscillations (200–1000 Hz) have been identified as possible signature markers of epileptogenic activity and may be involved in generating seizures. Moreover, a range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A–type potassium channel (KA). Our first objective was to investigate if KA could suppress synchronized input while minimally affecting desynchronised input. The second objective was to investigate if KA could suppress fast ripple activity. To study this I use a detailed compartmental model of a hippocampal CA1 pyramidal cell. The ion channels were described by Hodgkin–Huxley dynamics.The result showed that KA selectively could suppress highly synchronized input. I further used two models of fast ripple input and both models showed a strong reduction in the cellular spiking activity when KA was present. In an ongoing in vitro brain slice experiment our prediction from the simulations is being tested. Preliminary results show that the cellular response was reduced by 30 % for synchronised input, thus confirming our theoretical predictions. By suppressing fast ripples KA may prevent the highly synchronised spiking activity to spread and thereby preventing the seizure. Many antiepileptic drugs down regulate cell excitability by targeting sodium channels or GABA–receptors. These antiepileptic drugs affect the cell during normal brain activity thereby causing significant side effects. KA mainly suppresses the spiking activity when the cell is exposed to abnormally high synchronised input. An enhancement in the KA current might therefore be beneficial in reducing seizures while not affecting normal brain activity.