Y. Xia et al., Increased neuronal excitability after long-term O-2 deprivation is mediated mainly by sodium channels, MOL BRAIN R, 76(2), 2000, pp. 211-219
We have previously observed that prolonged O-2 deprivation alters membrane
protein expression and membrane properties in the central nervous system. I
n this work, we studied the effect of prolonged O-2 deprivation on the elec
trical activity of rat cortical and hippocampal neurons during postnatal de
velopment and its relationship to Na+ channels. Rats were raised in low O-2
environment (inspired O-2 concentration = 9.5 +/- 0.5%) for 3-4 weeks, sta
rting at an early age (2-3 days old). Using electrophysiologic recordings i
n brain slices, RNA analysis (northern and slot blots) and saxitoxin (a spe
cific ligand for Na+ channels) binding autoradiography, we addressed two qu
estions: (1) does long-term O-2 deprivation alter neuronal excitability in
the neocortical and hippocampal neurons during postnatal development? and (
2) if so, what are the main mechanisms responsible for the change in excita
bility in the exposed brain? Our results show that (i) baseline membrane pr
operties of cortical and hippocampal CAI neurons from rats chronically expo
sed to hypoxia were not substantially different from those of naive neurons
; (ii) acute stress (e.g., hypoxia) elicited a markedly exaggerated respons
e in the exposed neurons as compared to naive ones; (iii) chronic hypoxia t
ended to increase Na+ channel mRNA and saxitoxin binding density in the cor
tex and hippocampus as compared to control ones; and (iv) the enhanced neur
onal response to acute hypoxia in the exposed cortical and CA1 neurons was
considerably attenuated by applying tetrodotoxin, a voltage-sensitive Na+ c
hannel blocker, in a dose-dependent manner. We conclude that prolonged O-2
deprivation can lead to major electrophysiological disturbances, especially
when exposed neurons are stressed acutely, which renders the chronically e
xposed neurons more vulnerable to subsequent micro-environmental stress. We
suggest that this Na+ channel-related over-excitability is likely to const
itute a molecular mechanism for some neurological sequelae, such as epileps
y, resulting from perinatal hypoxic encephalopathy. (C) 2000 Elsevier Scien
ce B.V. All rights reserved.