Dataset Information

Association between GABA(A) receptor subunit gene cluster and zolpidem-induced complex sleep behaviors in Han Chinese.

ABSTRACT: STUDY OBJECTIVES: To investigate and elucidate the role of GABA(A) receptor subunits, specifically the 2 genetic markers at the GABA(A) ?1 and GABA(A) ?6 receptors, in zolpidem-induced complex sleep behaviors (CSBs). DESIGN: Genetic association study. SETTING: Kaohsiung Medical University-affiliated hospitals, Kaohsiung, Taiwan. PATIENTS: 30 zolpidem-induced CSB subjects and 37 controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: The ?(2) test demonstrated an association between the A15G variant at the GABA(A) ?1 receptor subunit gene and zolpidem-induced CSBs (P = 0.007). The adjusted odds ratio of the GABA(A) ?1 receptor subunit genotype for the risk of zolpidem-induced CSBs was approximately 10 (OR = 9.99, 95% CI = 1.82, 74.87; P = 0.013). CONCLUSIONS: The finding reveals that the A15G variant at the GABA(A) ?1 receptor subunit gene confers a high risk of zolpidem-induced CSBs and may be considered in clinical services.

SUBMITTER: Tsai JH

PROVIDER: S-EPMC3543054 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Association between GABA(A) receptor subunit gene cluster and zolpidem-induced complex sleep behaviors in Han Chinese.

Tsai Jui-Hsiu JH Yang Pinchen P Lin Hung-Hsun HH Cheng Kuang-Hung KH Yang Yi-Hsin YH Wu Ming-Tsang MT Chen Cheng-Chung CC

Sleep 20130201 2

<h4>Study objectives</h4>To investigate and elucidate the role of GABA(A) receptor subunits, specifically the 2 genetic markers at the GABA(A) α1 and GABA(A) α6 receptors, in zolpidem-induced complex sleep behaviors (CSBs).<h4>Design</h4>Genetic association study.<h4>Setting</h4>Kaohsiung Medical University-affiliated hospitals, Kaohsiung, Taiwan.<h4>Patients</h4>30 zolpidem-induced CSB subjects and 37 controls.<h4>Interventions</h4>N/A.<h4>Measurements and results</h4>The χ(2) test demonstrated ...[more]

PMID: 23372267

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Project description:Recently developed pharmacogenetic and optogenetic approaches, with their own advantages and disadvantages, have become indispensable tools in modern neuroscience. Here, we employed a previously described knock-in mouse line (GABA(A)R?2(77I)lox) in which the ?2 subunit of the GABA(A) receptor (GABA(A)R) was mutated to become zolpidem insensitive (?2(77I)) and used viral vectors to swap ?2(77I) with wild-type, zolpidem-sensitive ?2 subunits (?2(77F)). The verification of unaltered density and subcellular distribution of the virally introduced ?2 subunits requires their selective labelling. For this we generated six N- and six C-terminal-tagged ?2 subunits, with which cortical cultures of GABA(A)R?2(?/?) mice were transduced using lentiviruses. We found that the N-terminal AU1 tag resulted in excellent immunodetection and unimpaired synaptic localization. Unaltered kinetic properties of the AU1-tagged ?2 ((AU1)?2(77F)) channels were demonstrated with whole-cell patch-clamp recordings of spontaneous IPSCs from cultured cells. Next, we carried out stereotaxic injections of lenti- and adeno-associated viruses containing Cre-recombinase and the (AU1)?2(77F) subunit (Cre-2A-(AU1)?2(77F)) into the neocortex of GABA(A)R?2(77I)lox mice. Light microscopic immunofluorescence and electron microscopic freeze-fracture replica immunogold labelling demonstrated the efficient immunodetection of the AU1 tag and the normal enrichment of the (AU1)?2(77F) subunits in perisomatic GABAergic synapses. In line with this,miniature and action potential-evoked IPSCs whole-cell recorded from transduced cells had unaltered amplitudes, kinetics and restored zolpidem sensitivity. Our results obtained with a wide range of structural and functional verification methods reveal unaltered subcellular distributions and functional properties of ?2(77I) and (AU1)?2(77F) GABA(A)Rs in cortical pyramidal cells. This transgenic–viral pharmacogenetic approach has the advantage that it does not require any extrinsic protein that might endow some unforeseen alterations of the genetically modified cells. In addition, this virus-based approach opens up the possibility of modifying multiple cell types in distinct brain regions and performing alternative recombination-based intersectional genetic manipulations.

Dataset Information

Association between GABA(A) receptor subunit gene cluster and zolpidem-induced complex sleep behaviors in Han Chinese.

Publications

Association between GABA(A) receptor subunit gene cluster and zolpidem-induced complex sleep behaviors in Han Chinese.

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