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Subunit-Specific Effects of Isoflurane on Neuronal I_h in HCN1 Knockout Mice

¹Departments of Pharmacology and ²Anesthesiology, University of Virginia, Charlottesville, Virginia

Submitted 15 October 2008; accepted in final form 21 October 2008

The ionic mechanisms that contribute to general anesthetic actions have not been elucidated, although increasing evidence has pointed to roles for subthreshold ion channels, such as the HCN channels underlying the neuronal hyperpolarization-activated cationic current (I_h). Here, we used conventional HCN1 knockout mice to test directly the contributions of specific HCN subunits to effects of isoflurane, an inhalational anesthetic, on membrane and integrative properties of motor and cortical pyramidal neurons in vitro. Compared with wild-type mice, residual I_h from knockout animals was smaller in amplitude and presented with HCN2-like properties. Inhibition of I_h by isoflurane previously attributed to HCN1 subunit-containing channels (i.e., a hyperpolarizing shift in half-activation voltage [V_1/2]) was absent in neurons from HCN1 knockout animals; the remaining inhibition of current amplitude could be attributed to effects on residual HCN2 channels. We also found that isoflurane increased temporal summation of excitatory postsynaptic potentials (EPSPs) in cortical neurons from wild-type mice; this effect was predicted by simulation of anesthetic-induced dendritic I_h inhibition, which also revealed more prominent summation accompanying shifts in V_1/2 (an HCN1-like effect) than decreased current amplitude (an HCN2-like effect). Accordingly, anesthetic-induced EPSP summation was not observed in cortical cells from HCN1 knockout mice. In wild-type mice, the enhanced synaptic summation observed with low concentrations of isoflurane contributed to a net increase in cortical neuron excitability. In summary, HCN channel subunits account for distinct anesthetic effects on neuronal membrane properties and synaptic integration; inhibition of HCN1 in cortical neurons may contribute to the synaptically mediated slow-wave cortical synchronization that accompanies anesthetic-induced hypnosis.

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