ABSTRACT General anesthetics reduce cortical activity and disrupt consciousness, yet the molecular mechanisms underlying their effects on neocortical neurons remain incompletely understood. Recent evidence implicates layer 5 pyramidal neurons (L5 PNs) as critical targets, particularly through anesthetic‐induced decoupling of distal apical dendritic inputs from somatic output. While several anesthetics impair L5 excitability, the ion channels mediating this effect have yet to be clearly identified. Voltage‐gated Kv1.2 potassium channels have emerged as compelling candidates due to their high expression in L5 PNs and their known potentiation by volatile anesthetics. In this study, we investigated the effects of low‐dose sevoflurane (~22 μM) on L5 PNs in the primary auditory cortex of adult mice using whole‐cell patch‐clamp recordings. Sevoflurane significantly suppressed firing and induced cell‐type‐specific changes in membrane properties: depolarizing the resting potential in type A neurons and increasing input resistance and altering action potential shape in type B neurons. Application of the selective Kv1.2 blocker TsTX‐Kα partially reversed these effects at subthreshold membrane potentials, implicating Kv1.2 channel potentiation in the modulation of neuronal excitability. Supporting that view, NEURON simulations using a detailed biophysical model of thick‐tufted L5b pyramidal neurons further revealed a significant sevoflurane‐induced increase in persistent K + conductance, consistent with Kv1.2 potentiation. To our knowledge, this is the first study to demonstrate distinct, cell‐type‐specific effects of sevoflurane on L5 PNs and to establish the functional relevance of Kv1.2 channel potentiation in anesthetic suppression of cortical excitability. These findings offer new insights into the molecular actions of sevoflurane and support a broader role for Kv1.2 channels in mediating anesthetic‐induced outcomes. image
Araujo et al. (Thu,) studied this question.