Abstract
Astrocytes have been promoted as a possible mechanistic target for anaesthetic hypnosis. The aim of this study was to explore this using the neocortical brain slice preparation. The methods were in two parts. Firstly, multiple general anaesthetic compounds demonstrating varying in vivo hypnotic potency were analysed for their effect on “zero-magnesium” seizure-like event (SLE) activity in mouse neocortical slices. Subsequently, the effect of astrocyte metabolic inhibition was investigated in neocortical slices, and compared with that of the anaesthetic drugs. The rationale was that, if suppression of astrocytes was both necessary and sufficient to cause hypnosis in vivo, then inhibition of astrocytic metabolism in slices should mimic the anaesthetic effect. In vivo anaesthetic potency correlated strongly with the magnitude of reduction in SLE frequency in neocortical slices (R2 37.7 %, p = 0.002). Conversely, SLE frequency and length were significantly enhanced during exposure to both fluoroacetate (23 and 20 % increase, respectively, p < 0.01) and aminoadipate (12 and 38 % increase, respectively, p < 0.01 and p < 0.05). The capacity of an anaesthetic agent to reduce SLE frequency in the neocortical slice is a good indicator of its in vivo hypnotic potency. The results do not support the hypothesis that astrocytic metabolic inhibition is a mechanism of anaesthetic hypnosis.
Highlights
Understanding how anaesthetics cause loss of consciousness is of critical importance to both clinical anesthesiologists and neuroscientists—for both safer clinical application and understanding the biological basis of consciousness
We found that the in vivo hypnotic potency of the ketamine-esters correlated with their ability to reduce the frequency of zero-magnesium seizure-like events (SLEs) in the slice
Part 1 results: correlating in vivo hypnotic potency with cortical slice electrophysiology A large range of hypnotic potencies were represented in the suite of ketamine-ester analogues, matched by variable slice SLE responses
Summary
Understanding how anaesthetics cause loss of consciousness (hypnosis) is of critical importance to both clinical anesthesiologists and neuroscientists—for both safer clinical application and understanding the biological basis of consciousness. Thrane et al (2012) have recently shown that a chemically diverse group of anaesthetics inhibit astrocytic calcium signalling—the basis of astrocytic glutamatergic regulation of neuronal synaptic activity (Parpura and Haydon 2000). In vivo models are not ideally suited for disentangling anaesthetic hypnotic mechanisms because of the challenge of isolating the effects of interest in a controlled fashion. The isolated brain slice preparation is a case in point and has been used extensively to investigate mechanisms of anaesthetic effect (Antkowiak and Heck 1997; Becker et al 2012; Ries and Puil 1999; Ying et al 2006). In this study we have taken advantage of these effects to investigate whether a disruption to astrocytic networks can explain the functional anaesthetic end-point of hypnosis
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