Effect of chronically elevated CO2 on CA1 neuronal excitability

To study the effect of chronically elevated CO2 on the excitability and function of neurons, we exposed mice to 7.5-8% CO2 for similar to2 wk (starting at 2 days of age) and examined the properties of freshly dissociated hippocampal neurons. Neurons from control mice (CON) and from mice exposed to chronically elevated CO2 had similar resting membrane potentials and input resistances. CO2-exposed neurons, however, had a lower rheobase and a higher Na+ current density (580+/-73 pA/pF; n=27 neurons studied) than did CON neurons (280+/-51 pA/pF, n=34; P<0.01). In addition, the conductance-voltage curve was shifted in a more negative direction in CO2-exposed than in CON neurons (midpoint of the curve was -46 +/- 3 mV for CO2 exposed and -34 +/- 3 mV for CON, P<0.01), while the steady-state inactivation curve was shifted in a more positive direction in CO2-exposed than in CON neurons (midpoint of the curve was -59+/-2 mV for CO2 exposed and -68+/-3 mV for CON, P<0.01). The time constant for deactivation at -100 mV was much smaller in CO2-exposed than in CON neurons (0.8 +/- 0.1 ms for CO2 exposed and 1.9 +/- 0.3 ms for CON, P<0.01). Immunoblotting for Na+ channel proteins (subtypes I, II, and III) was performed on the hippocampus. Our data indicate that Na+ channel subtype I, rather than subtype II or III, was significantly increased (43%, n=4; P<0.05) in the hippocampi of CO2-exposed mice. We conclude that in mice exposed to elevated CO2, 1) increased neuronal excitability is due to alterations in Na+ current and Na+ channel characteristics, and 2) the upregulation of Na+ channel subtype I contributes, at least in part, to the increase in Na+ current density.