Hyperekplexia disease is usually caused by naturally occurring point mutations in glycine receptors (GlyRs). However, the γ-aminobutyric acid type A receptor (GABAR) seems to be also involved regarding the therapeutic basis for hyperekplexia using benzodiazepines, which target GABARs but not GlyRs. Here, we show that the function of GABARs was significantly impaired in the hypoglossal nucleus of hyperekplexic transgenic mice. Such impairment appeared to be mediated by interaction between GABAR and mutant GlyR. The GABAR dysfunction was caused only by mutant GlyR consisting of homomeric α subunits, which locate primarily at pre- and extra-synaptic sites. In addition, the rescue effects of diazepam were attenuated by Xli-093, which specifically blocked diazepam-induced potentiation on α-containing GABAR, a major form of pre- and extra-synaptic GABAR in the brainstem. Thus, our results suggest that the pre- and extra-synaptic GABARs could be a potential therapeutic target for hyperekplexia disease caused by GlyR mutations.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715904 | PMC |
| http://dx.doi.org/10.1016/j.isci.2019.08.018 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Post-synaptic GABA receptors potentiate transmission by recruiting CaV2 channels to their inputs.
Cell Rep
October 2023
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA. Electronic address:
We describe a retrograde synaptic signal at the C. elegans GABAergic neuromuscular junction. At this synapse, GABA release is controlled by two voltage-activated calcium channels (UNC-2/CaV2 and EGL-19/CaV1), and muscle responses are mediated by a single GABA receptor (UNC-49/GABA).
View Article and Find Full Text PDFHigh-Resolution Fluorescence Imaging Combined With Computer Simulations to Quantitate Surface Dynamics and Nanoscale Organization of Neuroligin-1 at Synapses.
Front Synaptic Neurosci
April 2022
CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297, University of Bordeaux, Bordeaux, France.
Neuroligins (NLGNs) form a family of cell adhesion molecules implicated in synapse development, but the mechanisms that retain these proteins at synapses are still incompletely understood. Recent studies indicate that surface-associated NLGN1 is diffusionally trapped at synapses, where it interacts with quasi-static scaffolding elements of the post-synaptic density. Whereas single molecule tracking reveals rapid diffusion and transient immobilization of NLGN1 at synapses within seconds, fluorescence recovery after photobleaching experiments indicate instead a long-term turnover of NLGN1 at synapse, in the hour time range.
View Article and Find Full Text PDFSubsynaptic Distribution, Lipid Raft Targeting and G Protein-Dependent Signalling of the Type 1 Cannabinoid Receptor in Synaptosomes from the Mouse Hippocampus and Frontal Cortex.
Molecules
November 2021
Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128 Mainz, Germany.
Numerous studies have investigated the roles of the type 1 cannabinoid receptor (CB1) in glutamatergic and GABAergic neurons. Here, we used the cell-type-specific CB1 rescue model in mice to gain insight into the organizational principles of plasma membrane targeting and Gαi/o protein signalling of the CB1 receptor at excitatory and inhibitory terminals of the frontal cortex and hippocampus. By applying biochemical fractionation techniques and Western blot analyses to synaptosomal membranes, we explored the subsynaptic distribution (pre-, post-, and extra-synaptic) and CB1 receptor compartmentalization into lipid and non-lipid raft plasma membrane microdomains and the signalling properties.
View Article and Find Full Text PDFNeuronal excitatory-to-inhibitory balance is altered in cerebral organoid models of genetic neurological diseases.
Mol Brain
October 2021
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, 59840, USA.
The neuro-physiological properties of individuals with genetic pre-disposition to neurological disorders are largely unknown. Here we aimed to explore these properties using cerebral organoids (COs) derived from fibroblasts of individuals with confirmed genetic mutations including PRNP, trisomy 21 (T21), and LRRK2, which are associated with Creutzfeldt Jakob disease, Down Syndrome, and Parkinson's disease. We utilized no known disease/healthy COs (HC) as normal function controls.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!