Journal of Neuroscience, Vol 9, 1223-1232, Copyright © 1989 by Society for Neuroscience
Roles for mitotic history in the generation and degeneration of hippocampal neuroarchitecture
MP Mattson, PB Guthrie, BC Hayes and SB Kater
Program in Neuronal Growth & Development, Colorado State University, Fort Collins 80523.
The mechanisms regulating the highly ordered neuroarchitecture of the
mammalian brain are largely unknown. The present study took advantage of
hippocampal pyramidal-like neurons that arose from a common progenitor cell
in cell culture (sister neurons) to ascertain the contribution of intrinsic
factors to both the generation and degeneration of neuroarchitecture.
Sister neurons were similar in overall cell form and dendritic numbers and
lengths. Control non-sister neurons that grew in contact did not generate
similar morphologies, indicating that the similarity of sister cells did
not result from influences of the local microenvironment or cell
interactions. These results suggest that intrinsic factors related to
mitotic history play a role in the generation of neuroarchitecture. Since
particular groups of hippocampal neurons are sensitive to glutamate
neurotoxicity in situ and are vulnerable in neurodegenerative disorders, it
was of interest to test glutamate sensitivity in the neuronal population
and in mitotic sister neurons. A subpopulation of pyramidal neurons was
sensitive to glutamate neurotoxicity. A striking finding was that sister
neurons were invariably either both sensitive or both resistant to
glutamate, while non-sister neurons often showed different responses to
glutamate. Pharmacological studies indicated that glutamate neurotoxicity
was mediated by kainate/quisqualate type receptors by a mechanism involving
calcium influx through membrane channels. Fura-2 measurements of
intracellular calcium revealed that sister neurons had similar rest levels
of calcium and, strikingly, glutamate caused a dramatic increase in
intracellular calcium levels only in neurons which subsequently
degenerated. Apparently, intrinsic differences in sensitivity to glutamate
lie at a point prior to calcium entry, probably at the level of glutamate
receptors. Taken together, these results indicate that the mitotic history
of a neuron can determine its presence and potential for connectivity as
well as its susceptibility to neurodegeneration.