Increased neuronal excitability after long-term O-2 deprivation is mediated mainly by sodium channels

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.