Thalamic T-Type Calcium Channels as Targets for Hypnotics and General Anesthetics.

Slobodan M Todorovic,Tamara Timic Stamenic

doi:10.3390/ijms23042349

Abstract

General anesthetics mainly act by modulating synaptic inhibition on the one hand (the potentiation of GABA transmission) or synaptic excitation on the other (the inhibition of NMDA receptors), but they can also have effects on numerous other proteins, receptors, and channels. The effects of general anesthetics on ion channels have been the subject of research since the publication of reports of direct actions of these drugs on ion channel proteins. In particular, there is considerable interest in T-type voltage-gated calcium channels that are abundantly expressed in the thalamus, where they control patterns of cellular excitability and thalamocortical oscillations during awake and sleep states. Here, we summarized and discussed our recent studies focused on the CaV3.1 isoform of T-channels in the nonspecific thalamus (intralaminar and midline nuclei), which acts as a key hub through which natural sleep and general anesthesia are initiated. We used mouse genetics and in vivo and ex vivo electrophysiology to study the role of thalamic T-channels in hypnosis induced by a standard general anesthetic, isoflurane, as well as novel neuroactive steroids. From the results of this study, we conclude that CaV3.1 channels contribute to thalamocortical oscillations during anesthetic-induced hypnosis, particularly the slow-frequency range of δ oscillations (0.5–4 Hz), by generating “window current” that contributes to the resting membrane potential. We posit that the role of the thalamic CaV3.1 isoform of T-channels in the effects of various classes of general anesthetics warrants consideration.

Highlights

Since their discoveries, T-type calcium channels (T-channels) have been studied in the context of thalamocortical oscillatory behavior, synaptic plasticity, cell excitability, and involvement in rebound burst-firing [1,2,3]
Slow-δ and α oscillations are dominant EEG signatures for propofol-induced anesthesia, which is a finding consistent with EEG patterns observed with other intravenous anesthetics targeting GABAA receptors
The similarities between the EEG patterns of GABAA-receptor-targeting anesthetics, propofol, and volatile general anesthetics seem to include the enhancement of GABAA-receptor-mediated inhibitory postsynaptic currents [66]

Summary

Introduction

T-type calcium channels (T-channels) have been studied in the context of thalamocortical oscillatory behavior, synaptic plasticity, cell excitability, and involvement in rebound burst-firing [1,2,3]. The stimulation of the central thalamus (including the mediodorsal and intralaminar nucleus) in monkeys during the unconscious state caused the reversal of neurophysiological signs of the hypnotic state [32] Consistent with this idea, microinjections of general anesthetics into the CeM region in rodents was shown to facilitate hypnosis, while injections of an antibody against voltage-gated potassium channels promoted arousal and the reversal of anesthetic-induced hypnosis [33,34]. Clinical studies have shown that deep brain stimulation of adjacent nuclei in the nonspecific central thalamus improved the state of consciousness in patients with severe brain injury [35] This motivated us to investigate the role of the CaV3.1 isoform of T-channels in regulating excitability states of the CeM and its role in neurosteroid-induced hypnosis and general anesthesia [36,37]. Our studies focused on rodents with reference to humans and nonhuman primates

Electroencephalographic Patterns during Unconsciousness and Anesthesia

Human Data

Animal Data

Summary