Voltage-gated potassium (Kv) channels are important regulators of normal neuronal function. In neurons, membrane excitability is regulated through Kv channels by maintaining or returning the cell to resting membrane potential and by modulating action potential threshold, duration, and frequency. Kv channels are composed of tetramers of pore-forming transmembrane subunits that associate with tetramers of cytoplasmic beta (beta) subunits. Alterations in Kv channels or their auxiliary beta subunits have been shown to affect neuronal processes such as long term potentiation (LTP) and neuronal excitability that are thought to be cellular correlates of learning and memory (L&M). Kvbeta2, the most abundant Kvbeta subunit in the brain, is a functional aldo-ketoreductase (AKR) and its catalytic activity has been linked to the regulation of K+ current. The role of Kvbeta2 in L&M, neuronal excitability, and LTP was examined using two strains of mice, one with a targeted deletion of the gene encoding Kvbeta2 (Kcnab2) and the other with a single amino acid mutation in Kvbeta2 that abolishes AKR catalytic activity (Y9OF point mutant). I demonstrated that Kvbeta2 null mice are impaired in spatial and emotional learning. Though these mice exhibited normal LTP in the hippocampus and the amygdala, they were shown to have increased neuronal excitability in the amygdala as measured by spike accommodation and post burstafterhyperpolarization. These results indicate that Kvbeta2 is an important regulator of neuronal excitability and that the loss of this function in vivo may contribute to the observed L&M impairment in Kvbeta2 null mice. For the Y90F point mutant mice, impairment in spatial learning and memory emerged only in aged mice in the absence of changes in LTP in the amygdala. These results indicate that the loss of AKR catalytic activity does not significantly contribute to the phenotype of Kvbeta2 null mice in spatial and emotional learning at a young age. However, once aged, Y90F point mutant mice exhibit similar learning deficits as young Kvbeta2 null mice, potentially indicating a role for an age-related increase in oxidative stress in the emergence of the Y90F point mutant phenotype.Ph.D.Biological SciencesNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/127098/2/3354051.pd
