Selective inhibition of gamma aminobutyric acid release from mouse hippocampal interneurone subtypes by the volatile anaesthetic isoflurane

Br J Anaesth. 2021 Oct;127(4):587-599. doi: 10.1016/j.bja.2021.06.042. Epub 2021 Aug 10.

Abstract

Background: The cellular and molecular mechanisms by which general anaesthesia occurs is poorly understood. Hippocampal interneurone subpopulations, which are critical regulators of cognitive function, have diverse neurophysiological and synaptic properties, but their responses to anaesthetics are unclear.

Methods: We used live-cell imaging of fluorescent biosensors expressed in mouse hippocampal neurones to delineate interneurone subtype-specific effects of isoflurane on synaptic vesicle exocytosis. The role of voltage-gated sodium channel (Nav) subtype expression in determining isoflurane sensitivity was probed by overexpression or knockdown of specific Nav subtypes in identified interneurones.

Results: Clinically relevant concentrations of isoflurane differentially inhibited synaptic vesicle exocytosis: to 83.1% (11.7%) of control in parvalbumin-expressing interneurones, and to 58.6% (13.3%) and 64.5% (8.5%) of control in somatostatin-expressing interneurones and glutamatergic neurones, respectively. The relative expression of Nav1.1 (associated with lower sensitivity) and Nav1.6 (associated with higher sensitivity) determined the sensitivity of exocytosis to isoflurane.

Conclusions: Isoflurane inhibits synaptic vesicle exocytosis from hippocampal glutamatergic neurones and GABAergic interneurones in a cell-type-specific manner depending on their expression of voltage-gated sodium channel subtypes.

Keywords: GABA; exocytosis; glutamate; interneurone; isoflurane; synaptic transmission; synaptic vesicle; voltage-gated sodium channel.

MeSH terms

  • Anesthetics, Inhalation / pharmacology*
  • Animals
  • Exocytosis / drug effects
  • Female
  • Gene Knockdown Techniques
  • Hippocampus / drug effects*
  • Hippocampus / metabolism
  • Isoflurane / pharmacology*
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / metabolism
  • Synaptic Transmission / drug effects
  • Voltage-Gated Sodium Channels / genetics
  • gamma-Aminobutyric Acid / metabolism*

Substances

  • Anesthetics, Inhalation
  • Voltage-Gated Sodium Channels
  • gamma-Aminobutyric Acid
  • Isoflurane