Examining the role of the M-type potassium current in epilepsy using mice that carry KCNQ2 and KCNQ3 gene alterations

Benign Familial Neonatal Convulsions (BFNC) is a human pediatric epilepsy characterized by seizure onset in the first few weeks of life and spontaneous resolution after about 2-4 months. It is considered benign because neuronal development and cognitive abilities are not adversely affected; however, BFNC patients have a 10-fold greater risk of developing adult onset epilepsy than the general public. BFNC is caused by mutations in the KCNQ2 and KCNQ3 genes, which encode the KCNQ2 and KCNQ3 subunits. These subunits underlie the M-type K+ channel (M channel), the outward K+ conductance of which generates the M current [Ik(m>] in neurons. Ik(m> is tonically active at resting membrane potential, and activates in response to membrane depolarization to repolarize the cell membrane. It thereby modulates resting membrane potential and regulates neuronal excitability. It has been assumed that mutations in the KCNQ2 and KCNQ3 genes that precipitate BFNC do so by decreasing Ik(m) function; however, no direct link between KCNQ2/KCNQ3 mutation and altered Ik(m) function has been established. The studies conducted in this dissertation were designed to better address this relationship. We hypothesize that mice carrying Kcnq2 and Kcnq3 gene mutations exhibit evidence of increased neuronal excitability. To test this hypothesis, we used three mouse models of Kcnq mutation to study whole-animal seizure thresholds and single-cell biophysical properties in CA1 hippocampal neurons. We have established that mice carrying Kcnq alterations indeed display reduced Ik(m) function, with corresponding hyperexcitability that is detectable at single-cell and whole-animal levels. We have also detailed several differences in M channel pharmacology that closely parallel differences in whole-animal pharmacosensitivity. The results presented in this dissertation are the first to detail reductions in native neuronal Ik(m) function, as well as increased single-cell neuroexcitability, that result from the expression of BFNC-causing mutations. These whole-animal behavioral and single-cell biophysical studies further confirm the link between attenuated Ik(m) function and increase seizure susceptibility that can result from Kcnq2 and Kcnq3 mutation.Kcnq3 mutation.