Changes in learning and memory (L&M) occur with aging, but little is known about their underlying molecular and cellular causes. Mice show age-related social transmission of food preference (STFP), and contextual conditioning. Remarkably, a mull mutation of the K+ channel auxiliary subunit Kvbeta1.1 improves L&M in these tasks, specifically in aged mice. In contrast, this mutation either impaired or had no effect in the performance of young mice in these tasks. Consistent with the hypothesis that an increased slow after-hyperpolarization (sAHP) contributes to age- related L&M deficits, the sAHO of the aged Kvbeta1.1 mutants is comparable to that of young wild type (WT) mice, but significantly smaller than aged Wts.
The specific aims of this proposal are: To further characterize the behavioral determinants underlying the rescue of L&M in aged Kvbeta1.1-/- mutant mice. To determine the time course for the L&M improvements triggered by the Kvbeta1.1.-/- mutation. To identify the electrophysiological mechanisms underlying the rescue of hippocampal-dependent L&M in the Kvbeta1.12.-/- mutants. To derive mice with neural specific and inducible mutations of Kvbeta1.1. The studies proposed here will not only further our understanding of the role of kvbeta1.1. in age-dependent L&M, but they will also be crucial for developing strategies to overcome these L&M impairments. Additionally, these studies will further our understanding of the possible connections between sAHP, LTP and L&M.
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| Murphy, Geoffrey G; Rahnama, Nancy P; Silva, Alcino J (2006) Investigation of age-related cognitive decline using mice as a model system: behavioral correlates. Am J Geriatr Psychiatry 14:1004-11 |
| Murphy, Geoffrey G; Fedorov, Nikolai B; Giese, K Peter et al. (2004) Increased neuronal excitability, synaptic plasticity, and learning in aged Kvbeta1.1 knockout mice. Curr Biol 14:1907-15 |
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| Anagnostaras, Stephan G; Murphy, Geoffrey G; Hamilton, Susan E et al. (2003) Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci 6:51-8 |
