Chronic hypoxia in vivo renders neocortical neurons more vulnerable to subsequent acute hypoxic stress

We studied the neurophysiology of neurons from the central nervous system (CNS) of rats that were exposed to a long-term (3-4 weeks) low oxygen (FiO2 = 9.5 +/- 0.5%) environment (exposed). Age-matched normoxic animals served as controls (naive). We measured membrane potential (Vm) and input resistance (Rm) at rest and in response to two levels (20% and 0% O2) of acute in vitro hypoxia using intracellular recordings in the brain slice from two areas of the CNS, layer 2/3 of the neocortex (NCX) and the hypoglossal nucleus in the brainstem (XII). Resting Vm and Rm were not different between exposed and naive neurons. However, acute hypoxia elicited dramatic differences between exposed and naive NCX neurons. Exposed NCX depolarized 5 x more (delta Vm = 53.2 +/- 7.0 mV; n = 13; mean +/- S.E.M.) than naive NCX (delta Vm = 10.6 +/- 2.0; n = 8) in response to 20% O2. In 0% O2, naive NCX showed anoxic depolarization (delta Vm > 20 mV/min) much sooner (mean latency of 4.8 +/- 0.4 min; n = 18) than naive NCX (8.8 +/- 1.0 min; n = 19). Rm decreased 2-4 times more in exposed NCX compared to naive NCX in response to O2 deprivation. In addition, while all naive NCX recovered to baseline Vm and Rm when re-oxygenated, exposed NCX exhibited a much slower recovery compared to naive NCX, and almost 20% of the exposed NCX failed to recover Vm and Rm following in vitro hypoxia. In contrast to NCX, there was little difference between exposed XII and naive XII. We conclude that chronic hypoxia renders neurons in the neocortex more vulnerable to subsequent acute stress such as O2 deprivation.