Advisory Committee Chair
John J Hablitz
Advisory Committee Members
Lucas Pozzo-Miller
Lori L McMahon
Linda Wadiche
Jeff Engler
Document Type
Dissertation
Date of Award
2012
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
Hyperpolarization activated non-specifc cation (HCN) channels are unique channels that activate following membrane hyperpolarization. Expressed primarily along the apical dendrites of pyramidal neurons, they pass a non-inactivating, inward current (Ih). HCN channel activation at resting membrane potentials profoundly impacts the synaptic and intrinsic properties of pyramidal neurons. Activated channels decrease intrinsic membrane excitability, hyperpolarize the resting membrane potential, and increase excitatory post-synaptic potentials (EPSP) summation. Loss of HCN channels is commonly observed in models of epilepsy. This dissertation tests the hypothesis that the influence of HCN channels on individual neuron excitability translates to an influence on network excitability. Furthermore, we hypothesize that loss of HCN channels in a model of malformation epilepsy contributes to observed hyperexcitability. We found that rats with freeze induced cortical lesions, a well-established model of malformation epilepsy, have reduced Ih, significantly increased EPSP summation, and increased membrane excitability. Using voltage sensitive dye imaging, we found that freeze lesioned rats exhibit significantly increased network excitability. Inhibiting HCN channels with ZD 7288 similarly increases network activation. Enhancing HCN channels with the anticonvulsant lamotrigine reduces network excitability. The ability of lamotrigine to reduce network excitability is significantly reduced in freeze lesioned rats. We next examined whether HCN channels influence epileptiform network events. Epileptiform events were evoked in situ using strong stimulation in disinhibited acute cortical slices. We found that HCN channel inhibition significantly increases the area of epileptiform events in pyramidal neurons from layers 5 and 2/3 and well as interneurons from layers 5 and 1. Interesting, ZD 7288 also increases the number of action potentials overlying epileptiform events, but only in layer five pyramidal neurons. This increase in area is mimicked when neurons are voltage clamped at -60 mV indicating that the increase in area is a network effect. We also found reduced Ih in layer 5 interneurons in freeze lesioned rats. ZD 7288 increases summation in layer 5 interneurons from control, but not lesioned rats. HCN channel inhibition decreases interneuron membrane excitability, and rats with freeze lesions have reduced baseline membrane excitability.
Recommended Citation
Albertson, Asher, "HCN Channels and Regulation of Neocortical Network Activity" (2012). All ETDs from UAB. 987.
https://digitalcommons.library.uab.edu/etd-collection/987