Inward rectifier potassium current IKir promotes intrinsic pacemaker activity of thalamocortical neurons

Abstract

Slow repetitive burst firing by hyperpolarized thalamocortical (TC) neurons correlates with global slow rhythms (<4 Hz), which are the physiological oscillations during non-rapid eye movement sleep or pathological oscillations during idiopathic epilepsy. The pacemaker activity of TC neurons depends on the expression of several subthreshold conductances, which are modulated in a behaviorally dependent manner. Here we show that upregulation of the small and neglected inward rectifier potassium current I_Kir induces repetitive burst firing at slow and delta frequency bands. We demonstrate this in mouse TC neurons in brain slices by manipulating the Kir maximum conductance with dynamic clamp. We also performed a thorough theoretical analysis that explains how the unique properties of I_Kir enable this current to induce slow periodic bursting in TC neurons. We describe a new ionic mechanism based on the voltage- and time-dependent interaction of I_Kir and hyperpolarization-activated cationic current I_h that endows TC neurons with the ability to oscillate spontaneously at very low frequencies, even below 0.5 Hz. Bifurcation analysis of conductance-based models of increasing complexity demonstrates that I_Kir induces bistability of the membrane potential at the same time that it induces sustained oscillations in combination with I_h and increases the robustness of low threshold-activated calcium current I_T-mediated oscillations. NEW & NOTEWORTHY The strong inwardly rectifying potassium current I_Kir of thalamocortical neurons displays a region of negative slope conductance in the current-voltage relationship that generates potassium currents activated by hyperpolarization. Bifurcation analysis shows that I_Kir induces bistability of the membrane potential; generates sustained subthreshold oscillations by interacting with the hyperpolarization-activated cationic current I_h; and increases the robustness of oscillations mediated by the low threshold-activated calcium current I_T. Upregulation of I_Kir in thalamocortical neurons induces repetitive burst firing at slow and delta frequency bands (<4 Hz).

Keywords: Kir channels; repetitive burst firing; subthreshold conductances; thalamocortical neurons.