Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits

Manzo, Marc A.; Wang, Dian-Shi; Li, Winston W.; Pinguelo, Arsène; Popa, M. Oana; Khodaei, Shahin; Atack, John; Ross, Ruth A.; Orser, Beverley A.

doi:10.1016/j.bja.2020.11.032

Cited by 9 publications

(5 citation statements)

References 46 publications

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“…Moreover, no differences were also seen in mean mIPSC frequency or amplitude between any SD and non-SD groups (p > 0.05; Fig 2D, E). The concentration of TTX (200 nM) we used is low, but the amplitudes of mIPSCs in our sample are comparable to other studies where 200 nM 10 or 500 nM 11 concentration was utilized. Findings suggest that SD impaired GABAergic tonic inhibition in the epileptic mice but not in seizure naïve mice and phasic inhibition was unaffected by SD.…”

Section: Sleep Deprivation Diminished the Magnitude Of Gabaergic Toni...supporting

confidence: 79%

Sleep Deprivation Exacerbates Seizures and Diminishes GABAergic Tonic Inhibition

Konduru

Pan

Wallace

et al. 2021

Annals of Neurology

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Patients with epilepsy report that sleep deprivation is a common trigger for breakthrough seizures. The basic mechanism of this phenomenon is unknown. In the Kv1.1−/− mouse model of epilepsy, daily sleep deprivation indeed exacerbated seizures though these effects were lost after the third day. Sleep deprivation also accelerated mortality in ~ 52% of Kv1.1−/− mice, not observed in controls. Voltage‐clamp experiments on the day after recovery from sleep deprivation showed reductions in GABAergic tonic inhibition in dentate granule cells in epileptic Kv1.1−/− mice. Our results suggest that sleep deprivation is detrimental to seizures and survival, possibly due to reductions in GABAergic tonic inhibition. ANN NEUROL 2021;90:840–844

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Section: Sleep Deprivation Diminished the Magnitude Of Gabaergic Toni...supporting

confidence: 79%

Sleep Deprivation Exacerbates Seizures and Diminishes GABAergic Tonic Inhibition

Konduru

Pan

Wallace

et al. 2021

Annals of Neurology

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“… Bai et al (2001) proposed that, for some anesthetics, tonic inhibition mediated by GABA A R acts in concert with synaptic inhibition mediated by other mechanisms to suppress hippocampal function during anesthesia. Several previous studies have also implicated GABA A R-mediated increases in tonic inhibitory conductance in a variety of cognitive psychiatric disorders (Down syndrome, schizophrenia, and Alzheimer’s, among others) ( Caraiscos et al, 2004 ; Manzo et al, 2021 ). Caraiscos et al (2004) declared that some anesthetics such as propofol, midazolam, and volatile anesthetics preferentially enhance tonic currents compared with synaptic currents.…”

Section: Anesthesia Exposure Causes Developmental Brain Damagementioning

confidence: 93%

“…These all strongly suggest that GABA A R-mediated tonic inhibition plays a key role in anesthesia-induced abnormalities in cognitive function. At the same time, considering that cognitive and psychiatric disorders caused by tonic inhibition are mediated by GABA A R, negative allosteric modulators of these receptors are under intense investigation ( Manzo et al, 2021 ). The α2 adrenergic receptor agonist, dexmedetomidine, has been extensively studied due to its neuroprotective effects.…”

Section: Anesthesia Exposure Causes Developmental Brain Damagementioning

confidence: 99%

Effect of Anesthesia on Oligodendrocyte Development in the Brain

Zhu

Zeng

et al. 2022

Front. Syst. Neurosci.

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Oligodendrocytes (OLs) participate in the formation of myelin, promoting the propagation of action potentials, and disruption of their proliferation and differentiation leads to central nervous system (CNS) damage. As surgical techniques have advanced, there is an increasing number of children who undergo multiple procedures early in life, and recent experiments have demonstrated effects on brain development after a single or multiple anesthetics. An increasing number of clinical studies showing the effects of anesthetic drugs on the development of the nervous system may mainly reside in the connections between neurons, where myelin development will receive more research attention. In this article, we review the relationship between anesthesia exposure and the brain and OLs, provide new insights into the development of the relationship between anesthesia exposure and OLs, and provide a theoretical basis for clinical prevention of neurodevelopmental risks of general anesthesia drugs.

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“…Given the role of extrasynaptic GABA A receptors in various disorders, considerable effort is being made to develop new drugs that selectively target these receptors, including agonists, antagonists, positive allosteric modulators, and negative allosteric modulators. 93,94 In fact, the successful development of positive allosteric modulators that modify δ GABA A receptors (i.e., brexanolone, zuranolone) for the treatment of postpartum depression has provided tremendous impetus for developing drugs that modulate extrasynaptic GABA A receptors. 95 Interestingly, the development of α5GABA A R inhibitors with clinical effectiveness has proven challenging for medicinal chemists and pharmaceutical companies.…”

Section: Properties Of Extrasynaptic Gaba a Receptors Your Data Caref...mentioning

confidence: 99%

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

Orser

2024

Anesthesiology

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Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors. By Caraiscos VB, Elliott EM, You-Ten KE, Cheng VY, Belelli D, Newell JG, Jackson MF, Lambert JJ, Rosahl TW, Wafford KA, MacDonald JF, Orser BA. Proc Natl Acad Sci U S A 2004; 101:3662–7. Reprinted with permission. In this Classic Paper Revisited, the author recounts the scientific journey leading to a report published in the Proceedings of the National Academy of Sciences (PNAS) and shares several personal stories from her formative years and “research truths” that she has learned along the way. Briefly, the principal inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA), was conventionally thought to regulate cognitive processes by activating synaptic GABA type A (GABAA) receptors and generating transient inhibitory synaptic currents. However, the author’s laboratory team discovered a novel nonsynaptic form of tonic inhibition in hippocampal pyramidal neurons, mediated by extrasynaptic GABAA receptors that are pharmacologically distinct from synaptic GABAA receptors. This tonic current is highly sensitive to most general anesthetics, including sevoflurane and propofol, and likely contributes to the memory-blocking properties of these drugs. Before the publication in PNAS, the subunit composition of GABAA receptors that generate the tonic current was unknown. The team’s research showed that GABAA receptors containing the α5 subunit (α5GABAARs) generated the tonic inhibitory current in hippocampal neurons. α5GABAARs are highly sensitive to GABA, desensitize slowly, and are thus well suited for detecting low, persistent, ambient concentrations of GABA in the extracellular space. Interest in α5GABAARs has surged since the PNAS report, driven by their pivotal roles in cognitive processes and their potential as therapeutic targets for treating various neurologic disorders.

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Inhibition of a tonic inhibitory conductance in mouse hippocampal neurones by negative allosteric modulators of α5 subunit-containing γ-aminobutyric acid type A receptors: implications for treating cognitive deficits

Cited by 9 publications

References 46 publications

Sleep Deprivation Exacerbates Seizures and Diminishes GABAergic Tonic Inhibition

Sleep Deprivation Exacerbates Seizures and Diminishes GABAergic Tonic Inhibition

Effect of Anesthesia on Oligodendrocyte Development in the Brain

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

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