) An increase in voltage-sensitive Ca2+ channels (VSCCS) contributes to changes in neuronal function during aging, and may render vulnerability to neurodegeneration. Recent evidence indicates that cytosolic levels of the protein phosphatase, calcineurin (CaN), increase in the hippocampus with advanced age. Moreover, CaN inhibitors reduce VSCC currents in cultured hippocampal cells. As such, the proposed experiments will explore the novel hypothesis that age-related changes in CaN and VSCCs are functionally related. In the first set of studies, the partially dissociated (""""""""zipper"""""""") slice preparation in combination with the cell-attached patch clamp technique will be used to determine whether CaN inhibitors differentially affect hippocampal VSCC activity in aged and young adult rats. This preparation also permits the extraction of individual, physiologically-characterized neurons, with major dendritic processes intact, for subsequent RT-PCR analysis. In this manner, CaN MRNA levels and VSCC activity in the same cell can be used to determine if CaN (or CaN-regulated factors) and VSCCs change in the same direction with age. Finally, whole-cell recording and Ca2+ imaging will be applied to cultured hippocampal cells to determine if CaN regulates intracellular Ca2+ signalling by modulating VSCCS. Together, these studies should increase our understanding of the role of CaN in Ca2+ regulation and brain aging.
| Norris, Christopher M; Kadish, Inga; Blalock, Eric M et al. (2005) Calcineurin triggers reactive/inflammatory processes in astrocytes and is upregulated in aging and Alzheimer's models. J Neurosci 25:4649-58 |
| Norris, C M; Blalock, E M; Chen, K-C et al. (2002) Calcineurin enhances L-type Ca(2+) channel activity in hippocampal neurons: increased effect with age in culture. Neuroscience 110:213-25 |
| Foster, T C; Sharrow, K M; Masse, J R et al. (2001) Calcineurin links Ca2+ dysregulation with brain aging. J Neurosci 21:4066-73 |
