Mutation in the Plp gene alters the electrophysiologic properties of neurons in the nts

Proteolipid protein ( Plp ) gene mutations in rodents such as the myelin deficient rat (MD) are associated with severe CNS dysmyelination and death after 19d of life, which we found is associated with lethal hypoxic ventilatory depression. We have also shown expression of the Plp gene in neurons in the medulla including the nucleus tractus solitarius (nts) (Miller, 2003). We hypothesized that expression of the mutant PlpMD gene would adversely alter electrophysiological properties in neurons within the nts. Using whole cell patch clamp in 300 μm in vitro brainstem slices, we analyzed current voltage relationships in commissural nts neurons from MD and normal rats at 3 ages (P12–14, P18–21, and P22–24). We compared current at +50mV during the action potential peak (peak) and 10ms after the action potential (plateau). Our results show a significantly reduced current in MD neurons at P22–24 during plateau phase compared to control. However, younger MD rats did not differ from normal. Apamin blockade of SK currents and TEA blockade of BK currents revealed that these currents were significantly decreased in MD rats at P22–24, the age at which we found lethal hypoxic ventilatory depression. We speculate that loss of BK and SK channel function in the MD nts may effectively block normal central neural response to afferent sensory input from the carotid body and lead to ineffective ventilatory response to hypoxia. Supp by NMSS 3669