A Metabolic Mechanism for Anaesthetic Suppression of Cortical Synaptic Function in Mouse Brain Slices-A Pilot Investigation.

Logan J Voss,Jamie W Sleigh

doi:10.3390/ijms21134703

Abstract

Regulation of synaptically located ionotropic receptors is thought to be the main mechanism by which anaesthetics cause unconsciousness. An alternative explanation, which has received much less attention, is that of primary anaesthetic disruption of brain metabolism via suppression of mitochondrial proteins. In this pilot study in mouse cortical slices, we investigated the effect of disrupting cellular metabolism on tissue oxygen handling and cortical population seizure-like event (SLE) activity, using the mitochondrial complex I inhibitor rotenone, and compared this to the effects of the general anaesthetics sevoflurane, propofol and ketamine. Rotenone caused an increase in tissue oxygen (98 mmHg to 157 mmHg (p < 0.01)) before any measurable change in SLE activity. Thereafter, tissue oxygen continued to increase and was accompanied by a significant and prolonged reduction in SLE root mean square (RMS) activity (baseline RMS of 1.7 to 0.7 µV, p < 0.001) and SLE frequency (baseline 4.2 to 0.4 events/min, p = 0.001). This temporal sequence of effects was replicated by all three anaesthetic drugs. In conclusion, anaesthetics with differing synaptic receptor mechanisms all effect changes in tissue oxygen handling and cortical network activity, consistent with a common inhibitory effect on mitochondrial function. The temporal sequence suggests that the observed synaptic depression—as seen in anaesthesia—may be secondary to a reduction in cellular metabolic capacity.

Highlights

The idea that disruption to brain metabolism may be at least part of the causal mechanism of general anaesthesia is not new [1,2], but in recent times the hypothesis has been largely disregarded as research has focused on ion channel targets at synapses
We have developed a cerebrocortical model of general anaesthesia exploiting spontaneous, cortically generated paroxysmal activity in mouse brain slices exposed to zero-magnesium artificial cerebrospinal fluid
The change in oxygen preceded any observed effect on seizure-like event (SLE) activity by about 10–20 min

Summary

Introduction

The idea that disruption to brain metabolism may be at least part of the causal mechanism of general anaesthesia is not new [1,2], but in recent times the hypothesis has been largely disregarded as research has focused on ion channel targets at synapses. In particular, demands most of this energy [4]—and is highly sensitive to metabolic stress [5,6]—providing an alternative pathway by which anaesthetics could act on the brain to disrupt consciousness. Support for this hypothesis is more than just conjectural. The question arises: “Exactly how does the ‘metabolic component’ of anaesthetic mechanism of action tie in with the competing body of work that concentrates on disturbance of synaptic function as the primary mechanism of anaesthesia?” To answer this, both (synaptic and metabolic) components need to be measured and manipulated in the same experimental preparation

Objectives

Methods

Results