Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice
Delta Subunit-Containing Gamma-Aminobutyric Acid A Receptor Disinhibits Lateral Amygdala and Facilitates Fear Expression in Mice
复制标题
含有 Delta 亚基的 γ-氨基丁酸 A 受体抑制外侧杏仁核并促进小鼠的恐惧表达
DOI：
10.1016/j.biopsych.2016.06.022
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发表时间：
2017-06-15
影响因子：
10.6
通讯作者：
Pan, Bing-Xing
中科院分区：
文献类型：
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作者：
Liu, Zhi-Peng;He, Qing-Hai;Pan, Bing-Xing
背景技术背景：在生理范围内维持杏仁核中的γ-氨基丁酸能（GABA能）抑制对于适当表达情绪（如恐惧和焦虑）至关重要。突触GABA A型受体（GABA（A）R）通常已知介导杏仁核抑制的主要成分并防止恐惧的不适当表达。然而，关于突触外GABA（A）R在杏仁核抑制和恐惧中的作用却知之甚少。通过使用在中间神经元（IN）中表达绿色荧光蛋白并且缺乏仅位于突触外膜中的含有δ亚基的GABA（A）R（GABA（A）（δ）R）的小鼠，我们采用免疫组织化学、电生理学和行为学相结合的方法系统地研究了GABA（A）（delta）R在调节杏仁核外侧区（LA）抑制和恐惧学习中的作用。与突触GABA（A）R在介导LA抑制中的既定作用形成鲜明对比，我们发现，GABA（A）（delta）R的药理学或生理学募集导致LA投射神经元上的GABA能传递减弱，而突触能传递不变，表明GABA（A）（delta）R解除抑制。这种去抑制作用是由于GABA（A）（delta）R的激活降低了局部INs的输入阻抗并抑制了它们的激活。GABA（A）（delta）R的基因缺失减弱了其抑制LA INs和解除LA抑制的作用。重要的是，GABA（A）（δ）R促进长时程增强的感觉传入LA，并允许学习fear.CONCLUSIONS的表达：我们的研究结果表明，GABA（A）（δ）R作为一个刹车，而不是一个调解员的GABA能抑制LA。GABA（A）（delta）R的去抑制作用可能有助于防止杏仁核活动的过度抑制，从而确保情绪的表达。
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 (GABA(A)R) 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 GABA(A)R to amygdala inhibition and fear.METHODS: By using mice expressing green fluorescent protein in interneurons (INs) and lacking the delta subunit-containing GABA(A)R (GABA(A)(delta)R), which is exclusively situated in the extrasynaptic membrane, we systematically investigated the role of GABA(A)(delta)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 GABA(A)R in mediating LA inhibition, we found that either pharmacological or physiological recruitment of GABA(A)(delta)R resulted in the weakening of GABAergic transmission onto projection neurons in LA while leaving the glutamatergic transmission unaltered, suggesting disinhibition by GABA(A)(delta)R. The disinhibition arose from IN-specific expression of GABA(A)(delta)R with its activation decreasing the input resistance of local INs and suppressing their activation. Genetic deletion of GABA(A)(delta)R attenuated its role in suppressing LA INs and disinhibiting LA. Importantly, the GABA(A)(delta)R facilitated long-term potentiation in sensory afferents to LA and permitted the expression of learned fear.CONCLUSIONS: Our findings suggest that GABA(A)(delta)R serves as a brake rather than a mediator of GABAergic inhibition in LA. The disinhibition by GABA(A)(delta)R may help to prevent excessive suppression of amygdala activity and thus ensure the expression of emotion.