Differential contribution of the subthreshold operating currents I T , I h , and I Kir to the resonance of thalamocortical neurons.

Membrane potential oscillations of thalamocortical (TC) neurons are believed to be involved in the generation and maintenance of brain rhythms that underlie global physiological and pathological brain states. These membrane potential oscillations depend on the synaptic interactions of TC neurons and their intrinsic electrical properties. These oscillations may be also shaped by increased output responses at a preferred frequency, known as intrinsic neuronal resonance. Here, we combine electrophysiological recordings in mouse brain slices, modern pharmacological tools, dynamic clamp, and computational modeling to study the ionic mechanisms that generate and modulate TC neuron resonance. We confirm findings of pioneering studies showing that most TC neurons display resonance that results from the interaction of the slow inactivation of the low-threshold calcium current I _T with the passive properties of the membrane. We also show that the hyperpolarization-activated cationic current I _h is not involved in the generation of resonance; instead it plays a minor role in the stabilization of TC neuron impedance magnitude due to its large contribution to the steady conductance. More importantly, we also demonstrate that TC neuron resonance is amplified by the inward rectifier potassium current I _Kir by a mechanism that hinges on its strong voltage-dependent inward rectification (i.e., a negative slope conductance region). Accumulating evidence indicate that the ion channels that control the oscillatory behavior of TC neurons participate in pathophysiological processes. Results presented here points to I _Kir as a new potential target for therapeutic intervention. NEW & NOTEWORTHY Our study expands the repertoire of ionic mechanisms known to be involved in the generation and control of resonance and provides the first experimental proof of previous theoretical predictions on resonance amplification mediated by regenerative hyperpolarizing currents. In thalamocortical neurons, we confirmed that the calcium current I _T generates resonance, determined that the large steady conductance of the cationic current I _h curtails resonance, and demonstrated that the inward rectifier potassium current I _Kir amplifies resonance.