Calcium channel density and hippocampal cell death with age in long-term culture.
The expression of voltage-gated calcium (Ca2+) channel activity in brain cells is known to be important for several aspects of neuronal development. In addition, excessive Ca2+ influx has been linked clearly to neurotoxicity both in vivo and in vitro; however, the temporal relationship between the development of Ca2+ channel activity and neuronal survival is not understood. Over a period spanning 28 d in vitro, progressive increases in high voltage-activated whole-cell Ca2+ current and L-type Ca2+ channel activity were observed in cultured hippocampal neurons. On the basis of single-channel analyses, these increases seem to arise in part from a greater density of functionally available L-type Ca2+ channels. An increase in mRNA for the alpha1 subunit of L-type Ca2+ channels occurred over a similar time course, which suggests that a change in gene expression may underlie the increased channel density. Parallel studies showed that hippocampal neuronal survival over 28 d was inversely related to increasing Ca2+ current density. Chronic treatment of hippocampal neurons with the L-type Ca2+ channel antagonist 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 neurons. The results also are analogous to patterns seen in neurons of aged animals and therefore raise the possibility that long-term primary neuronal culture could serve as a model for some aspects of aging changes in hippocampal Ca2+ channel function.
Porter
N M
NM
University of Kentucky, Department of Pharmacology, College of Medicine, Lexington, Kentucky 40536, USA.
Thibault
O
O
Thibault
V
V
Chen
K C
KC
Landfield
P W
PW
D000818:Animals; D015220:Calcium Channels / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D006624:Hippocampus / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D013997:Time Factors
D015220:Calcium Channels