Suppression of Ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons

The contributions of the hyperpolarization-activated current, 1 h, to generation of rhythmic activities are well described for various central neurons, particularly in thalamocortical circuits. In the present study, we investigated effects of a general anesthetic, propofol, on native 1 h in neurons of thalamus and cortex and on the corresponding cloned HCN channel subunits. Whole cell voltage-clamp recordings from mouse brain slices identified neuronal 1 h currents with fast activation kinetics in neocortical pyramidal neurons and with slower kinetics in thalamocortical relay cells. Propofol inhibited the fast-activating 1 h in cortical neurons at a clinically relevant concentration (5 mu M); inhibition of 1 h involved a hyperpolarizing shift in half-activation voltage (Delta V1/2 approximately -9 mV) and a decrease in maximal available current (similar to 36% inhibition, measured at -120 mV). With the slower form of 1 h expressed in thalamocortical neurons, propofol had no effect on current activation or amplitude. In heterologous expression systems, 5 mu M propofol caused a large shift in V1/2 and decrease in current amplitude in homomeric HCN1 and linked heteromeric HCN1-HCN2 channels, both of which activate with fast kinetics but did not affect V1/2 or current amplitude of slowly activating homomeric HCN2 channels. With GABA A and glycine receptor channels blocked, propofol caused membrane hyperpolarization and suppressed action potential discharge in cortical neurons; these effects were occluded by the 1 h blocker, ZD-7288. In summary, these data indicate that propofol selectively inhibits HCN channels containing HCN1 subunits, such as those that mediate 1 h in cortical pyramidal neurons and they suggest that anesthetic actions of propofol may involve inhibition of cortical neurons and perhaps other HCN1-expressing cells.