Gabra5 plays a sexually dimorphic role in POMC neuron activity and glucose balance.
Gabra5 plays a sexually dimorphic role in POMC neuron activity and glucose balance.
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DOI：
10.3389/fendo.2022.889122
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发表时间：
2022
影响因子：
5.2
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中科院分区：
文献类型：
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前阿黑皮素（POMC）神经元对于体重和葡萄糖平衡的调节是重要的。POMC神经元的抑制性紧张主要由GABA受体介导。然而，GABA受体的详细机制和功能还不清楚。GABAA受体的α5亚基Gabra 5被报道调节摄食，并且我们发现Gabra 5在POMC神经元中高度表达。为了探索Gabra 5在POMC神经元中的功能，我们使用成簇规则间隔短回文重复序列（CRISPR）-Cas9策略从成熟的下丘脑POMC神经元特异性敲除Gabra 5。这种POMC特异性敲低Gabra 5不影响雄性或雌性小鼠的体重或食物摄入。有趣的是，Gabra 5的丢失导致放电频率和静息膜电位的显著增加，以及男性POMC神经元中的微型抑制性突触后电流（mIPSC）的振幅的降低。然而，Gabra 5的缺失仅适度降低了雌性POMC神经元中mIPSC的频率。一致的是，POMC特异性敲低Gabra 5显著改善雄性小鼠的葡萄糖耐量，但在雌性小鼠中没有。这些结果揭示了Gabra 5在POMC神经元活性和葡萄糖平衡中的性别二态性作用，与体重控制无关。
Pro-opiomelanocortin (POMC) neurons are important for the regulation of body weight and glucose balance. The inhibitory tone to POMC neurons is mediated primarily by the GABA receptors. However, the detailed mechanisms and functions of GABA receptors are not well understood. The α5 subunit of GABAA receptor, Gabra5, is reported to regulate feeding, and we found that Gabra5 is highly expressed in POMC neurons. To explore the function of Gabra5 in POMC neurons, we knocked down Gabra5 specifically from mature hypothalamic POMC neurons using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 strategy. This POMC-specific knock-down of Gabra5 did not affect body weight or food intake in either male or female mice. Interestingly, the loss of Gabra5 caused significant increases in the firing frequency and resting membrane potential, and a decrease in the amplitude of the miniature inhibitory postsynaptic current (mIPSC) in male POMC neurons. However, the loss of Gabra5 only modestly decreased the frequency of mIPSC in female POMC neurons. Consistently, POMC-specific knock-down of Gabra5 significantly improved glucose tolerance in male mice but not in female mice. These results revealed a sexually dimorphic role of Gabra5 in POMC neuron activity and glucose balance, independent of body weight control.