Abstract 338: Neuronal Responses to Hypoxic Stress in Mouse Cognitive Cortex

Cardiovascular disorders may cause hypoxic/ischemic injury to the cortex, leading to dysfunction of cortical cognition with a worse outcome in the older population. Although damage to cognitive cortex has been implicated in cognitive dysfunctions, the exact pathophysiology of a hypoxic/ischemic insult to this region is not well understood yet at the cellular and molecular levels. We used the whole-cell patch clamp in mouse slice preparations to characterize the basic electrophysiological properties of pyramidal cells of prefrontal cortex (PFC) and determine the response of these neurons to hypoxic stress in young adult (24±4 days old, n=7) and relatively older (42±12 days old, n=17) mice. In relatively older adult neurons (42±12 days old, n=17), the currents evoked by stepping from -140 mV to 20 mV (IV, holding at -60 mV) were shifted upward by hypoxic stress, indicating an increase in membrane conductance. Whole cell currents (holding at -60 mV) were found to decrease with a 3-min hypoxia, while increased with 5-min and 7-min hypoxia, suggesting that prolonged hypoxia increased open probability of ion channels. Resting membrane potential (MP) shifted upward in all three hypoxic conditions with a larger change seen with the longer duration of hypoxia. Action potentials (APs) showed the same tendency with 7-min hypoxia, showing a significant reduction in the number of hypoxia-stimulated pulses. However, all hypoxic conditions blocked the APs generation, suggesting hypoxic inhibition of neuronal excitability. In contrast, hypoxia-induced IV was apparently reversed in the younger neurons as compared to the older neurons, especially after 5 minutes of hypoxia (99.26 pA vs. -14.91 pA at -100 mV, P<0.01). Interestingly, even in normoxic condition, MP was significantly larger in young adult neurons (-74.38 mV) than in the older ones (-64.67 mV) (P<0.001). These data suggest that younger pyramidal cells of PFC are less vulnerable to hypoxic stress. Moreover, our preliminary data showed that activation of the delta-opioid receptors (DOR) inhibited the hypoxic response in the older neurons. Since acupuncture induces DOR up-regulation in the cortex, it is likely that acupuncture protects cortical neurons against hypoxic/ischemic stress via the DOR mechanism.