CALCIUM-CHANNEL DENSITY AND HIPPOCAMPAL CELL-DEATH WITH AGE IN LONG-TERM CULTURE

The expression of voltage-gated calcium (Ca2+) channel activity in bra in cells is known to be important for several aspects of neuronal deve lopment. In addition, excessive Ca2+ influx has been linked clearly to neurotoxicity both in vivo and in vitro; however, the temporal relati onship between the development of Ca2+ channel activity and neuronal s urvival is not understood. Over a period spanning 28 d in vitro, progr essive increases in high voltage-activated whole-cell Ca2+ current and L-type Ca2+ channel activity were observed in cultured hippocampal ne urons. On the basis of single-channel analyses, these increases seem t o arise in part from a greater density of functionally available L-typ e Ca2+ channels. An increase in mRNA for the alpha(1) subunit of L-typ e Ca2+ channels occurred dyer a similar lime course, which suggests th at a change in gene expression may underlie the increased channel dens ity. Parallel studies showed that hippocampal neuronal survival over 2 8 d was inversely related to increasing Ca2+ current density. Chronic treatment of hippocampal neurons with the L-type Ca2+ channel antagoni st nimodipine significantly enhanced survival. Together, these results suggest that age-dependent increases in the density of Ca2+ channels might contribute significantly to declining viability of hippocampal n eurons. The results also are analogous to patterns seen in neurons of aged animals and therefore raise the possibility that long-term primar y neuronal culture could serve as a model for some aspects of aging ch anges in hippocampal Ca2+ channel function.