School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, PR China.
School of Medicine, Jiangsu University, Zhenjiang, Jiangsu Province 212013, PR China.
Brain Res Bull. 2020 Apr;157:128-139. doi: 10.1016/j.brainresbull.2020.02.005. Epub 2020 Feb 11.
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-1α 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.
中间神经元不仅有助于皮质网络活动的全局平衡，还通过特定蛋白质来调节信息的精确传递。越来越多的证据表明，过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）集中在抑制性中间神经元中，并且在神经精神疾病中发挥重要作用。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照记忆中的功能仍不完全清楚。为了研究 PGC-1α 在精神障碍进展中的精确作用，我们首先通过 dlx5/6 启动子控制的 Cre 重组酶的转基因表达生成 PGC-1α 条件性敲除小鼠，Cre 介导的切除事件特异性地发生在 γ-氨基丁酸（GABA）能神经元中。使用新物体识别测试和 Morris 水迷宫测试评估 Dlx5/6-Cre::PGC-1α 小鼠的短期习惯化和空间参照记忆，通过声起始反射的预脉冲抑制测量感觉运动门控。通过 Western 印迹、免疫荧光和免疫组织化学研究特定脑区的 Parvalbumin（PV）蛋白表达。在这里，我们表明 GABA 能神经元中缺乏 PGC-1α 基因的小鼠表现出短期习惯化缺陷、过度活跃、预脉冲抑制减少和惊跳反应增强，但正常的联想空间参照记忆。特别是，这些小鼠表现出异常的显著性，即更多地关注原始物体的进一步副本（现在熟悉）（相对于原始物体的第一次呈现，以及相对于新物体的呈现）。这些行为功能障碍与皮质（包括体感和运动皮质）以及海马体中 PV 表达减少有关，特别是在 CA1 和 CA3 区。总之，这些发现引起了人们对 PGC-1α 条件性敲除小鼠高反应表型的关注，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因子，也是与 PGC-1α 失调相关的精神障碍的潜在治疗靶点。
