Epilepsy is a disease of abnormal neuronal excitability, but the causes of this hyperexcitability remain largely unknown. Our understanding of the intrinsic determinants of neuronal excitability has significantly improved in recent years due to technical advances which allow electrophysiological study of neuronal dendrites, such as those of CA1 hippocampal and neocortical pyramidal neurons. This proposal investigates the possibility that temporal lobe epilepsy is associated with altered biophysical properties of a voltage-gated channel, which is primarily localized to dendrites, the h-channel or Ih. Prior studies have found that Ih in hippocampal pyramidal neurons can be altered by a single prolonged seizure, and that Ih is a target of anticonvulsant action. We propose studying Ih in hippocampal pyramidal neuron dendrites to determine if its properties are altered in an animal model of chronic epilepsy. Because prior work by the PI and others has shown that dendritic Ih reduces overall pyramidal neuron excitability, our central hypothesis will be that Ih may be down-regulated in the dendrites of pyramidal neurons in epileptic animals, producing neuronal hyperexcitability. The studies proposed involve whole-cell and cell-attached patch clamp electrophysiology in the soma and dendrites of CA1 hippocampal pyramidal neurons prepared using brain slice techniques. Specifically, we will answer the following questions: 1) How is Ih modulated under normal conditions in pyramidal neuron dendrites? 2) Are Ih properties altered in pyramidal neuron dendrites from epileptic animals? 3) Is dendritic Ih differentially modulated in chronic epilepsy? These studies may provide further evidence for the hypothesis that epilepsy results in part from changes in the intrinsic excitability of neurons, and may suggest novel targets, such as the h-channel or its modulators, in the treatment of epilepsy. The PI has recently started a laboratory at the University of Washington devoted to cellular neurophysiology, and treats adults with epilepsy as part of the Regional Epilepsy Center there. If funded, this proposal will enable the PI's transition to an independent clinician-scientist with a career focus on both basic and clinical aspects of epilepsy.
| Jung, Sangwook; Bullis, James B; Lau, Ignatius H et al. (2010) Downregulation of dendritic HCN channel gating in epilepsy is mediated by altered phosphorylation signaling. J Neurosci 30:6678-88 |
