Deficits in learning and memory which arise independent of overt pathology are considered to be a normal component of aging. It is estimated that about 40% of people over the age of 65 years suffer from some sort of age-related cognitive impairment. The exact nature of the underlying neuronal changes that give rise to these naturally occurring age-related learning and memory deficits remains unknown. However, in recent years several promising hypotheses have emerged. Prominent among them is the """"""""calcium dysregulation hypothesis of brain aging and neuro-degeneration."""""""" This hypothesis asserts that a number of age-related changes in neuronal function are the result of a dysregulation in the homeostasis of cytosolic free calcium. Indeed there is significant experimental evidence demonstrating an elevated level of intracellular calcium in the neurons of aged animals during neuronal activity. Furthermore, there are several lines of converging evidence that suggest that the increase in calcium is due to an increase in the number of L-type voltage-sensitive calcium channels (L-VSCC), and this increase in calcium channel density is correlated with a decrease in performance in spatial learning ability and working memory. Taken collectively, the evidence outlined above is compelling; however, the hypothesis that an age-related up-regulation of neuronal LVSCC expression can actually cause cognitive impairment has yet to be tested directly. To directly test this hypothesis, we have generated transgenic mice in which the neuronal L-type calcium channel subunit Cav1.3 can be over-expressed in an inducible, cell-type and region-specific manner. In young transgenic animals, over-expression of Cav1.3 would be expected to produce a selective and premature cognitive impairment. The overall effort of this proposal will be to: 1) complete the initial characterization of these mice at the molecular and biochemical level, and 2) complete the initial behavioral characterization. These transgenic mice are expected to advance our knowledge on two fronts. First, they will allow us to test directly the hypothesis that age-related increases in calcium channels can give rise to the cognitive impairments that often accompany aging. Second, if this hypothesis is indeed correct, these mice will then become an invaluable tool in the development of therapies targeting the amelioration of age-related cognitive impairments that arise from up-regulation of calcium channel expression.
| Gamelli, Amy E; McKinney, Brandon C; White, Jessica A et al. (2011) Deletion of the L-type calcium channel Ca(V) 1.3 but not Ca(V) 1.2 results in a diminished sAHP in mouse CA1 pyramidal neurons. Hippocampus 21:133-41 |
| McKinney, B C; Schneider, J S; Schafer, G L et al. (2008) Decreased locomotor activity in mice expressing tTA under control of the CaMKII alpha promoter. Genes Brain Behav 7:203-13 |
| White, Jessica A; McKinney, Brandon C; John, Manorama C et al. (2008) Conditional forebrain deletion of the L-type calcium channel Ca V 1.2 disrupts remote spatial memories in mice. Learn Mem 15:1-5 |
| McKinney, Brandon C; Murphy, Geoffrey G (2006) The L-Type voltage-gated calcium channel Cav1.3 mediates consolidation, but not extinction, of contextually conditioned fear in mice. Learn Mem 13:584-9 |
