Focal cortical dysplasia is associated with the development of seizures in children and is present in up to 40% of intractable childhood epilepsies. Transcortical freeze-lesions in the newborn rat reproduce many of the anatomical and electrophysiological characteristics of human focal cortical dysplasias. Although abnormalities in several voltage-dependent currents have been implicated in epilepsy, changes in intrinsic excitability have not been extensively investigated in cortical dysplasia. The broad goal of this proposal is to identify mechanisms whereby alterations in HCN channel expression in specific cell types contribute to hyperexcitability in cortical dysplasia. The role of HCN channels in generation and modulation of synchronized epileptic network activity is poorly understood. Ictal discharges in human dysplastic cortex are partially dependent on synchronous GABA mediated events. The role of HCN channels in modulation of GABAergic interneuron excitability has received little attention. We will test the hypothesis that specific subclasses o layer 5 (L5) pyramidal neurons in dysplastic cortex have changes in intrinsic excitability and hyper-excitable dendrites due to decreases in HCN channels. The mechanism underlying increased excitability will be determined by quantifying changes in currents co-expressed in these cells (Kir and M-currents) and known to be modified in other models of epilepsy. We will also test the hypothesis that (1) excitability of GABAergic interneurons is modulated by HCN channels and that (2) decreases in HCN expression alters intrinsic excitability and temporal summation in identified subtypes of inhibitory interneurons in cortical dysplasia. Finally, we will test if Ih modulates synchronization in GABAergic interneuron networks. It is hypothesized that Ih inhibition will enhance interneuron network activity and this will be altered in cortical dysplasia. Overall, we will provide new information on HCN modulation of cellular and network properties in cortical dysplasia and elucidate how HCN channels influence signaling in GABAergic neurons and networks.
Neocortical epilepsy related to focal cortical dysplasia (FCD) is one of the most common drug- resistant focal epilepsies in humans. This project will generate important new information concerning the role of hyperpolarization-activated, non-selective cation (HCN) channels in the development of hyperexcitability in an animal model of FCD Results will provide new insights into mechanisms underlying hyperexcitability in FCD and test novel therapeutic strategies for control.
|Williams, Sidney B; Hablitz, John J (2015) Differential modulation of repetitive firing and synchronous network activity in neocortical interneurons by inhibition of A-type K(+) channels and Ih. Front Cell Neurosci 9:89|