GABAA receptors are the major inhibitory neurotransmitter receptors in the brain. They are heteropentamers that are typically classified according to their α subunits. By rendering each of the benzodiazepine-sensitive α subunits (α1, α2, α3, and α5) insensitive to modulation by classical benzodiazepines by His to Arg point mutations in knock-in mice, we were able to identify behavioral functions mediated by different GABAA receptor subtypes, which led to the development of novel therapeutic strategies. In this chapter, we provide a largely chronological overview on behavioral studies on GABAA receptor mutant mice at the Institute of Pharmacology and Toxicology at the University of Zurich.
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http://dx.doi.org/10.1016/bs.apha.2014.10.001 | DOI Listing |
Background: Type 2 diabetes mellitus (T2DM) is associated with a greater risk of Alzheimer's disease (AD). Synaptic impairment and protein aggregates have been reported in the brains of T2DM rodent models. Here, we assessed the changes in synaptic vesicle 2A (SV2A), amyloid-β, and tau that are featured pathologies in AD in T2DM rats in vivo.
View Article and Find Full Text PDFAlzheimers Dement
December 2024
Centre for Addiction and Mental Health, Toronto, ON, Canada.
Background: Dysregulated GABA/somatostatin (SST) signaling has been implicated in psychiatric and neurodegenerative disorders. The inhibition of excitatory neurons by SST+ interneurons, particularly through α5-containing GABAA receptors (α5-GABAAR), plays a crucial role in mitigating cognitive functions. Previous research demonstrated that an α5-positive allosteric modulator (α5-PAM) mitigates working memory deficits and reverses neuronal atrophy in aged mice.
View Article and Find Full Text PDFInflamm Res
January 2025
Medical Faculty and University Hospital, Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, 40225, Düsseldorf, Germany.
Background: Adenosine, an ATP degradation product, is a sleep pressure factor. The adenosine 1 receptor (A1R) reports sleep need. Histaminergic neurons (HN) of the tuberomamillary nucleus (TMN) fire exclusively during wakefulness and promote arousal.
View Article and Find Full Text PDFAnesth Analg
November 2024
From the Department of Anesthesia Critical Care & Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts.
Background: R-Glabridin is a major flavonoid of licorice (Glycyrrhiza glabra) root and known to modulate GABAA receptors, which are targets of many clinical hypnotics. However, R-glabridin hypnotic activity has not been reported in animals.
Methods: Inverted photomotor responses (IPMRs) were used to assess the hypnotic effects of natural R-glabridin and synthetic R/S-glabridin in wild-type zebrafish larvae and transgenic larvae lacking functional GABAA receptor β3 subunits (β30/0).
Sci Adv
January 2025
SciLifeLab, Department of Applied Physics, KTH Royal Institute of Technology, Tomtebodävagen 23, Solna, 17165 Stockholm, Sweden.
γ-Aminobutyric acid type A (GABA) receptors are ligand-gated ion channels in the central nervous system with largely inhibitory function. Despite being a target for drugs including general anesthetics and benzodiazepines, experimental structures have yet to capture an open state of classical synaptic α1β2γ2 GABA receptors. Here, we use a goal-oriented adaptive sampling strategy in molecular dynamics simulations followed by Markov state modeling to capture an energetically stable putative open state of the receptor.
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