The long-term objective of this project is to elucidate the neuronal mechanisms that underlie age-related deficiencies in learning and memory. Recently, our laboratory has created a strain of mice in which the Kvbeta1.1 subunit of the potassium channel has been deleted. Deletion of the Kvbeta1.1 subunit produced impairments in hippocampus-dependent learning in young Kvbeta1.1 mutants. Remarkably, aged (greater than 18 mo.) Kvbeta1.1 mutants showed no such impairment and do not exhibit the age-related memory deficits normally seen in age-matched wild-type mice.
The specific aims of this proposal are to 1. Further characterize the learning behavior of these mice, using a combination of well established behavioral paradigms (i.e. Morris water maze and Pavlovian fear conditioning) and 2. Investigate the neuronal mechanisms that underlie the absence of age-related learning deficits in the aged Kvbeta1.1 mutants. Specifically, electrophysiological experiments will be conducted to explore the possibility that the Kvbeta1.1. mutants might exhibit alterations in neuronal excitability and how these alterations might affect specific forms of synaptic plasticity thought to mediate learning and memory. The proposed research will serve as the basis for improving our understanding of age-related changes in human learning and memory and thereby help in the amelioration of cognitive decline in the elderly.
|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; Shah, Vaibhavi; Hell, Johannes W et al. (2006) Investigation of age-related cognitive decline using mice as a model system: neurophysiological correlates. Am J Geriatr Psychiatry 14:1012-21|
|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|
|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|