Interneurons not only contribute to the global balance of activity in cortical networks but also mediate the precise gating of information through specific proteins. Accumulating evidence demonstrates that peroxisome-proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1α) is concentrated in inhibitory interneurons and that it plays an important role in neuropsychiatric diseases. However, the functions of the transcriptional coactivator PGC-1α in sensorimotor gating, short-term habituation and spatial reference memory are still not entirely clear. To investigate the precise involvement of PGC-1α in the progression of psychiatric disorders, we first generated PGC-1α conditional knockout mice through transgenic expression of Cre recombinase under the control of dlx5/6 promoter, Cre-mediated excision events occurred specifically in γ-amino-butyric-acid-(GABA)ergic neurons. Short-term habituation and spatial reference memory in Dlx5/6-Cre::PGC-1αfl/fl mice were evaluated using the novel object recognition test and the Morris water maze test, and sensorimotor gating was measured by prepulse inhibition of the acoustic startle reflex. Protein expression of parvalbumin (PV) in specific brain regions was studied by western blotting, immunofluorescence and immunohistochemistry. Here, we show that mice lacking the PGC-1α gene in GABAergic neurons exhibit deficits in short-term habituation, hyperactivity, reduced prepulse inhibition and exaggerated startle reactivity but normal associative spatial reference memory. In particular, these mice display aberrant salience, whereby more attention is paid to a further copy of the original object (now familiar) (relative to the first presentation of the original object, and relative to the presentation of the novel object). These behavioral dysfunctions were associated with decreased PV expression in the cortex (including somatosensory and motor cortex) as well as in the hippocampus, especially in its CA1 and CA3 regions. Together, these findings draw attention to a hyper-response phenotype of PGC-1α conditional knockout mice and indicate that PGC-1α is a novel regulator of gene expression and function in PV-positive interneurons and a potential therapeutic target for psychiatric disorders associated with PGC-1α dysregulation.

中文翻译：

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成人条件性敲除 GABA 能神经元中的 PGC-1α 会导致过度的惊吓反应、短期习惯受损和多动。

中间神经元不仅有助于皮层网络活动的全球平衡，而且还通过特定蛋白质介导信息的精确门控。越来越多的证据表明，过氧化物酶体增殖物激活受体-γ 共激活物 1 α (PGC-1α) 集中在抑制性中间神经元中，并且它在神经精神疾病中起着重要作用。然而，转录共激活因子 PGC-1α 在感觉运动门控、短期习惯化和空间参考记忆中的功能仍不完全清楚。为了研究 PGC-1α 在精神疾病进展中的精确参与，我们首先在 dlx5/6 启动子的控制下通过 Cre 重组酶的转基因表达产生 PGC-1α 条件敲除小鼠，Cre 介导的切除事件专门发生在 γ-氨基-丁酸-(GABA) 能神经元中。使用新型物体识别测试和莫里斯水迷宫测试评估 Dlx5/6-Cre::PGC-1αfl/fl 小鼠的短期习惯和空间参考记忆，并通过声惊反射的前脉冲抑制测量感觉运动门控. 通过蛋白质印迹、免疫荧光和免疫组织化学研究了特定脑区小清蛋白 (PV) 的蛋白质表达。在这里，我们展示了 GABA 能神经元中缺乏 PGC-1α 基因的小鼠表现出短期习惯化、多动、减少前脉冲抑制和夸大惊吓反应性的缺陷，但关联空间参考记忆正常。特别是，这些老鼠表现出异常的显着性，从而更多地关注原始对象（现在熟悉）的进一步副本（相对于原始对象的第一次呈现，以及相对于新对象的呈现）。这些行为功能障碍与皮层（包括躯体感觉和运动皮层）以及海马体中 PV 表达的降低有关，尤其是在其 CA1 和 CA3 区域。总之，这些发现引起人们对 PGC-1α 条件性敲除小鼠的超反应表型的关注，并表明 PGC-1α 是 PV 阳性中间神经元中基因表达和功能的新型调节剂，也是与 PGC 相关的精神疾病的潜在治疗靶点-1α 失调。这些行为功能障碍与皮层（包括躯体感觉和运动皮层）以及海马体中 PV 表达的降低有关，尤其是在其 CA1 和 CA3 区域。总之，这些发现引起人们对 PGC-1α 条件性敲除小鼠的超反应表型的关注，并表明 PGC-1α 是 PV 阳性中间神经元中基因表达和功能的新型调节剂，也是与 PGC 相关的精神疾病的潜在治疗靶点-1α 失调。这些行为功能障碍与皮层（包括躯体感觉和运动皮层）以及海马体中 PV 表达的降低有关，尤其是在其 CA1 和 CA3 区域。总之，这些发现引起人们对 PGC-1α 条件性敲除小鼠的超反应表型的关注，并表明 PGC-1α 是 PV 阳性中间神经元中基因表达和功能的新型调节剂，也是与 PGC 相关的精神疾病的潜在治疗靶点-1α 失调。