GABAA Receptors in Astrocytes Are Targets for Commonly Used Intravenous and Inhalational General Anesthetic Drugs

Abstract

Background: Perioperative neurocognitive disorders (PNDs) occur commonly in older patients after anesthesia and surgery. Treating astrocytes with general anesthetic drugs stimulates the release of soluble factors that increase the cell-surface expression and function of GABAA receptors in neurons. Such crosstalk may contribute to PNDs; however, the receptor targets in astrocytes for anesthetic drugs have not been identified. GABAA receptors, which are the major targets of general anesthetic drugs in neurons, are also expressed in astrocytes, raising the possibility that these drugs act on GABAA receptors in astrocytes to trigger the release of soluble factors. To date, no study has directly examined the sensitivity of GABAA receptors in astrocytes to general anesthetic drugs that are frequently used in clinical practice. Thus, the goal of this study was to determine whether the function of GABAA receptors in astrocytes was modulated by the intravenous anesthetic etomidate and the inhaled anesthetic sevoflurane.Methods: Whole-cell voltage-clamp recordings were performed in astrocytes in the stratum radiatum of the CA1 region of hippocampal slices isolated from C57BL/6 male mice. Astrocytes were identified by their morphologic and electrophysiologic properties. Focal puff application of GABA (300 μM) was applied with a Picospritzer system to evoke GABA responses. Currents were studied before and during the application of the non-competitive GABAA receptor antagonist picrotoxin (0.5 mM), or etomidate (100 μM) or sevoflurane (532 μM).Results: GABA consistently evoked inward currents that were inhibited by picrotoxin. Etomidate increased the amplitude of the peak current by 35.0 ± 24.4% and prolonged the decay time by 27.2 ± 24.3% (n = 7, P < 0.05). Sevoflurane prolonged current decay by 28.3 ± 23.1% (n = 7, P < 0.05) but did not alter the peak amplitude. Etomidate and sevoflurane increased charge transfer (area) by 71.2 ± 45.9% and 51.8 ± 48.9% (n = 7, P < 0.05), respectively.Conclusion: The function of astrocytic GABAA receptors in the hippocampus was increased by etomidate and sevoflurane. Future studies will determine whether these general anesthetic drugs act on astrocytic GABAA receptors to stimulate the release of soluble factors that may contribute to PNDs.

Time to Wake Up! The Ongoing Search for General Anesthetic Reversal Agents

“…In addition to mitochondria, astrocytes present a wide range of likely general anesthetic targets that probably modulate emergence dynamics (see review 75 ) including even GABA A receptors. 143 Microglia, the immune cells of central nervous system, also appear to modulate emergence from sedation and analgesia thresholds. 144 The different pharmacodynamics of these diverse targets distributed among different cells surrounding a synapse may explain why reversal agents can accelerate certain behaviors but not others, and the time required for general anesthetics to dissociate from these multiple sites may contribute to delayed recovery.…”

Discovering the Intriguing Properties of Extrasynaptic γ-Aminobutyric Acid Type A Receptors

“…14 Equally intriguing was our recent finding that glia, and in particular, astrocytes-the most abundant cells in the brain-express anesthetic-sensitive extrasynaptic GABA A receptors. 77 Activation of astrocytic GABA A receptors by sevoflurane and etomidate triggers an astrocyte-toneuron crosstalk that increases the tonic current in neurons. Interestingly, both the anesthetic drugs and proinflammatory factors (e.g., IL-1β) engage the same cytosolic pathways to enhance cell surface expression of α5GABA A Rs.…”

Brain areas modulation in consciousness during sevoflurane anesthesia

“…A deeper knowledge of the formation of consciousness and the operation of different brain regions may result from research on the interplay between the two domains. Additionally, there is mounting proof that glial cells are involved and that sevoflurane acts on their GABA A receptors (Woll et al, 2018;Chung et al, 2022), thereby influencing their function. (2022) ↑indicated that the time is increasing, the EEG power increased or the c-Fos positive cells was increased.…”