Propofol decreases the excitability of cholinergic neurons in mouse basal forebrain via GABAA receptors

Chen, Lei; Yang, Zhilai; Cheng, Jiwei; Zhang, Pingping; Zhang, Lesha; Liu, Xuesheng; Wang, Liecheng

doi:10.1038/s41401-018-0168-6

Cited by 16 publications

(10 citation statements)

References 40 publications

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“…It is also worth noting that a majority of studies have focused on the mechanistic role of AMPARs and NMDARs in regulating LHb physiology, however there are a paucity of studies regarding how GABAARs are involved. Unlike other structures where exposure to propofol decreases neuronal excitability [35,36], this does not seem to be the case here. Interestingly, direct intra-LHb injections of GABAergic agonists and antagonists have been shown to decrease and increase LHb activity [37], respectively, indicating that GABAARs do indeed serve an inhibitory role within the LHb.…”

Section: Discussioncontrasting

confidence: 74%

Paradoxical excitation of lateral habenula neurons by propofol involves enhanced presynaptic release of glutamate

Shepard

Lü

2021

Preprint

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Sleep is a fundamental physiological process conserved across most species. As such, deficits in sleep can result in a myriad of psychological and physical health issues. However, the mechanisms underlying the induction of sleep are relatively unknown. Interestingly, general anesthetics cause unconsciousness by positively modulating GABA-A receptors (GABAARs). Based on this observation, it is hypothesized that GABAARs play a critical role in modulating circuits involved in sleep to promote unconsciousness. Recently, the lateral habenula (LHb) has been demonstrated to play a role in sleep physiology and sedation. Specifically, propofol has been shown to excite LHb neurons to promote sedation. However, the mechanism by which this occurs is unknown. Here, we utilize whole-cell voltage and current clamp recordings from LHb neurons obtained from 8-10 week old male mice to determine the physiological mechanisms for this phenomenon. We show that bath application of 1.5μM propofol is sufficient to increase LHb neuronal excitability involving synaptic transmission, but not through modulation of intrinsic properties. Additionally, although there is increased LHb neuronal excitability, GABAARs localized postsynaptically on LHb neurons are still responsive to propofol, as indicated by an increase in the decay time. Lastly, we find that propofol increases the synaptic drive onto LHb neurons involving enhanced presynaptic release of both glutamate and GABA. However, the greatest contributor to the potentiated synaptic drive is the increased release of glutamate which shifts the balance of synaptic transmission towards greater excitation. Taken together, this study is the first to identify the physiological basis for why LHb neurons are excited by propofol, rather than inhibited, and as a result promote sedation.

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Section: Discussioncontrasting

confidence: 74%

Paradoxical excitation of lateral habenula neurons by propofol involves enhanced presynaptic release of glutamate

Shepard

Lü

2021

Preprint

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“…In spite of this, the event of BF cholinergic neurons is rapidly and continuously inhibited during propofol anesthesia. A study on brain slices also confirmed that propofol could decrease the excitability of cholinergic neurons in the basal forebrain of mouse (Chen et al, 2019). These results suggest that the BF cholinergic system might serve as a critical target for the function of general anesthetics.…”

Section: Discussionmentioning

confidence: 67%

Basal Forebrain Cholinergic Activity Modulates Isoflurane and Propofol Anesthesia

et al. 2020

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Cholinergic neurons in the basal forebrain (BF) have long been considered to be the key neurons in the regulation of cortical and behavioral arousal, and cholinergic activation in the downstream region of the BF can arouse anesthetized rats. However, whether the activation of BF cholinergic neurons can induce behavior and electroencephalogram (EEG) recovery from anesthesia is unclear. In this study, based on a transgenic mouse line expressing ChAT-IRES-Cre, we applied a fiber photometry system combined with GCaMPs expression in the BF and found that both isoflurane and propofol inhibit the activity of BF cholinergic neurons, which is closely related to the consciousness transition. We further revealed that genetic lesion of BF cholinergic neurons was associated with a markedly increased potency of anesthetics, while designer receptor exclusively activated by designer drugs (DREADD)-activated BF cholinergic neurons was responsible for slower induction and faster recovery of anesthesia. We also documented a significant increase in δ power bands (1-4 Hz) and a decrease in β (12-25 Hz) power bands in BF cholinergic lesioned mice, while there was a clearly noticeable decline in EEG δ power of activated BF cholinergic neurons. Moreover, sensitivity to anesthetics was reduced after optical stimulation of BF cholinergic cells, yet it failed to restore wakelike behavior in constantly anesthetized mice. Our results indicate a functional role of BF cholinergic neurons in the regulation of general anesthesia. Inhibition of BF cholinergic neurons mediates the formation of unconsciousness induced by general anesthetics, and their activation promotes recovery from the anesthesia state.

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“…We previously found that the activity of cholinergic neurons in BF could influence propofol and isoflurane anesthesia process 16 . Furthermore, several studies have indicated that propofol decreases the activity of BF cholinergic neurons via GABA A receptors 17,18 …”

Section: Introductionmentioning

confidence: 99%

Effect of basal forebrain somatostatin and parvalbumin neurons in propofol and isoflurane anesthesia

et al. 2021

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Aims The basal forebrain (BF) plays an essential role in wakefulness and cognition. Two subtypes of BF gamma‐aminobutyric acid (GABA) neurons, including somatostatin‐expressing (GABASOM) and parvalbumin‐positive (GABAParv) neurons, function differently in mediating the natural sleep–wake cycle. Since the loss of consciousness induced by general anesthesia and the natural sleep–wake cycle probably share similar mechanisms, it is important to clarify the accurate roles of these neurons in general anesthesia procedure. Methods Based on two transgenic mouse lines expressing SOM‐IRES‐Cre and PV‐IRES‐Cre, we used a combination of genetic activation, inactivation, and chronic ablation approaches to further explore the behavioral and electroencephalography (EEG) roles of BFSOM and BFParv neurons in general anesthesia. After a single intravenous injection of propofol and the induction and recovery times of isoflurane anesthesia, the anesthesia time was compared. The changes in cortical EEG under different conditions were also compared. Results Activation of BF GABASOM neurons facilitates both the propofol and isoflurane anesthesia, manifesting as a longer anesthesia duration time with propofol anesthesia and a fast induction time and longer recovery time with isoflurane anesthesia. Moreover, BF GABASOM‐activated mice displayed a greater suppression of cortical electrical activity during anesthesia, showing an increase in δ power bands or a simultaneous decrease in high‐frequency power bands. However, only a limited and nuanced effect on propofol and isoflurane anesthesia was observed with the manipulated BF GABAParv neurons. Conclusions Our results suggested that BF GABASOM neurons play a critical role in propofol and isoflurane general anesthesia, while BF GABAParv neurons appeared to have little effect.

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Propofol decreases the excitability of cholinergic neurons in mouse basal forebrain via GABAA receptors

Cited by 16 publications

References 40 publications

Paradoxical excitation of lateral habenula neurons by propofol involves enhanced presynaptic release of glutamate

Paradoxical excitation of lateral habenula neurons by propofol involves enhanced presynaptic release of glutamate

Basal Forebrain Cholinergic Activity Modulates Isoflurane and Propofol Anesthesia

Effect of basal forebrain somatostatin and parvalbumin neurons in propofol and isoflurane anesthesia

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