Human Hyperekplexic Mutations in Glycine Receptors Disinhibit the Brainstem by Hijacking GABAA Receptors
Guichang Zou,
Qi Chen,
Kai Chen,
Xin Zuo,
Yushu Ge,
Yiwen Hou,
Tao Pan,
Huilin Pan,
Dan Liu,
Li Zhang,
Wei Xiong
Affiliations
Guichang Zou
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
Qi Chen
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
Kai Chen
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
Xin Zuo
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
Yushu Ge
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
Yiwen Hou
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
Tao Pan
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
Huilin Pan
Center for Neuroscience and Pain Research, Department of Anesthesiology and Perioperative Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Dan Liu
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
Li Zhang
Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
Wei Xiong
Hefei National Laboratory for Physical Sciences at the Microscale, Neurodegenerative Disorder Research Center, School of Life Sciences, University of Science and Technology of China, Hefei 230026, China; Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; Corresponding author
Summary: Hyperekplexia disease is usually caused by naturally occurring point mutations in glycine receptors (GlyRs). However, the γ-aminobutyric acid type A receptor (GABAAR) seems to be also involved regarding the therapeutic basis for hyperekplexia using benzodiazepines, which target GABAARs but not GlyRs. Here, we show that the function of GABAARs was significantly impaired in the hypoglossal nucleus of hyperekplexic transgenic mice. Such impairment appeared to be mediated by interaction between GABAAR and mutant GlyR. The GABAAR dysfunction was caused only by mutant GlyR consisting of homomeric α1 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 α5-containing GABAAR, a major form of pre- and extra-synaptic GABAAR in the brainstem. Thus, our results suggest that the pre- and extra-synaptic GABAARs could be a potential therapeutic target for hyperekplexia disease caused by GlyR mutations. : Neurogenetics; Molecular Interaction; Molecular Neuroscience Subject Areas: Neurogenetics, Molecular Interaction, Molecular Neuroscience
