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Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice

  • Author Footnotes
    1 Z-PL, Q-HH, T-MG, and B-XP contributed equally to the work.
    Zhi-Peng Liu
    Footnotes
    1 Z-PL, Q-HH, T-MG, and B-XP contributed equally to the work.
    Affiliations
    Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang
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  • Author Footnotes
    1 Z-PL, Q-HH, T-MG, and B-XP contributed equally to the work.
    Qing-Hai He
    Footnotes
    1 Z-PL, Q-HH, T-MG, and B-XP contributed equally to the work.
    Affiliations
    State Key Laboratory of Organ Failure Research, Key Laboratory of Psychiatric Disorders of Guangdong Province; Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou
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  • Han-Qing Pan
    Affiliations
    Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang
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  • Xiao-Bin Xu
    Affiliations
    Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang
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  • Wen-Bing Chen
    Affiliations
    Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang
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  • Ye He
    Affiliations
    Medical Experiment Center, Nanchang University, Nanchang
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  • Jin Zhou
    Affiliations
    Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang
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  • Wen-Hua Zhang
    Affiliations
    Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang
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  • Jun-Yu Zhang
    Affiliations
    Department of Biotechnology, School of Life Sciences, Nanchang University, Nanchang
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  • Xiao-Ping Ying
    Affiliations
    Department of Neurology, the 2nd Affiliated Hospital, , Nanchang University, Nanchang
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  • Ren-Wen Han
    Affiliations
    Institute of Translational Medicine, Nanchang University, Nanchang
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  • Bao-Ming Li
    Affiliations
    Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang
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  • Author Footnotes
    1 Z-PL, Q-HH, T-MG, and B-XP contributed equally to the work.
    Tian-Ming Gao
    Footnotes
    1 Z-PL, Q-HH, T-MG, and B-XP contributed equally to the work.
    Affiliations
    State Key Laboratory of Organ Failure Research, Key Laboratory of Psychiatric Disorders of Guangdong Province; Department of Neurobiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou
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  • Author Footnotes
    1 Z-PL, Q-HH, T-MG, and B-XP contributed equally to the work.
    Bing-Xing Pan
    Correspondence
    Address correspondence to: Bing-Xing Pan, Ph.D., M.D., Institute of Life Science, Laboratory of Fear and Anxiety Disorders, 1029 Xuefu Avenue, Nanchang, Jiangxi, China.
    Footnotes
    1 Z-PL, Q-HH, T-MG, and B-XP contributed equally to the work.
    Affiliations
    Laboratory of Fear and Anxiety Disorders, Institute of Life Science, Nanchang University, Nanchang

    Department of Neurology, the 2nd Affiliated Hospital, , Nanchang University, Nanchang

    Jiangxi Provincial Collaborative Innovation Center for Cardiovascular, Digestive and Neuropsychiatric Diseases, Jiangxi, China
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  • Author Footnotes
    1 Z-PL, Q-HH, T-MG, and B-XP contributed equally to the work.

      ABSTRACT

      Background

      Maintaining gamma-aminobutyric acidergic (GABAergic) inhibition in the amygdala within a physiological range is critical for the appropriate expression of emotions such as fear and anxiety. The synaptic GABA type A receptor (GABAAR) is generally known to mediate the primary component of amygdala inhibition and prevent inappropriate expression of fear. However, little is known about the contribution of the extrasynaptic GABAAR to amygdala inhibition and fear.

      Methods

      By using mice expressing green fluorescent protein in interneurons (INs) and lacking the δ subunit-containing GABAAR (GABAA(δ)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABAA(δ)R in regulating inhibition in the lateral amygdala (LA) and fear learning using the combined approaches of immunohistochemistry, electrophysiology, and behavior.

      Results

      In sharp contrast to the established role of synaptic GABAAR in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABAA(δ)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABAA(δ)R. The disinhibition arose from IN-specific expression of GABAA(δ)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABAA(δ)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABAA(δ)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear.

      Conclusions

      Our findings suggest that GABAA(δ)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABAA(δ)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion.

      Keywords

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