Ketamine Effects Are Mediated by Inhibition of I0h0

Ketamine inhibits NMDA receptors, but mice lacking an NMDA receptor subunit still exhibit the behavioral effects of ketamine, suggesting the drug may have other targets.

Indeed, this week Chen et al. report that the behavioral effects of ketamine are likely to result from inhibition of hyperpolarization-activated cyclic nucleotide–modulated (HCN1) cation channels.

These channels mediate Ih, the "sag" current that is activated by action potential after hyperpolarization and helps stabilize membrane potential, regulates spike frequency, and contributes to a dendritic shunt that causes nonlinear summation of EPSPs.

In pyramidal neurons in mouse cortical slices, ketamine inhibited Ih, caused a hyperpolarizing shift in resting membrane potential, and enhanced summation of excitatory currents—effects likely to produce cortical oscillations. Importantly, none of these effects, nor hypnotic effects in vivo, were produced in mice lacking HCN1 channels.

By Society for Neuroscience