A deficit of brain dystrophin impairs specific amygdala GABAergic transmission and enhances defensive behaviour in mice
A deficit of brain dystrophin impairs specific amygdala GABAergic transmission and enhances defensive behaviour in mice
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DOI：
10.1093/brain/awn253
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发表时间：
2009-01-01
期刊：
影响因子：
14.5
通讯作者：
Wada, Keiji
中科院分区：
文献类型：
--
作者：
Sekiguchi, Masayuki;Zushida, Ko;Wada, Keiji
杜氏肌营养不良症 (DMD) 伴有认知缺陷和精神症状。在大脑中，肌营养不良蛋白（负责 DMD 的蛋白质）定位于 GABA 能突触的一个子集，但其在大脑功能中的作用尚未完全得到解决。在这里，我们报告说，抗肌营养不良蛋白缺陷的 mdx 小鼠的防御行为（对危险或威胁的反应）得到增强。 Mdx 小鼠对短暂的束缚始终表现出强效的防御性冻结反应，而野生型小鼠从未诱导过此类反应。 mdx 小鼠对电击足部的无条件和条件防御反应也得到增强。 mdx小鼠在高架十字迷宫测试中的表现没有明显的异常，表明mdx小鼠的焦虑状态没有改变。我们发现，在 mdx 小鼠中，抗肌营养不良蛋白在杏仁核中表达，并且在基底外侧核 (BLA) 中，GABA(A) 受体 2 亚基簇的数量减少。在 mdx 小鼠中，BLA 锥体神经元中去甲肾上腺素诱导的 GABA 能抑制性突触电流的频率显着降低。吗啉代寡核苷酸诱导的截短肌营养不良蛋白在 mdx 小鼠大脑中表达，但在肌肉中则不然，改善了对约束的异常冻结反应。这些结果表明，脑肌营养不良蛋白的缺乏会引起杏仁核局部抑制神经元回路的改变，并增强小鼠因恐惧而引发的防御行为。
Duchenne muscular dystrophy (DMD) is accompanied by cognitive deficits and psychiatric symptoms. In the brain, dystrophin, the protein responsible for DMD, is localized to a subset of GABAergic synapses, but its role in brain function has not fully been addressed. Here, we report that defensive behaviour, a response to danger or a threat, is enhanced in dystrophin-deficient mdx mice. Mdx mice consistently showed potent defensive freezing responses to a brief restraint that never induced such responses in wild-type mice. Unconditioned and conditioned defensive responses to electrical footshock were also enhanced in mdx mice. No outstanding abnormality was evident in the performances of mdx mice in the elevated plus maze test, suggesting that the anxiety state is not altered in mdx mice. We found that, in mdx mice, dystrophin is expressed in the amygdala, and that, in the basolateral nucleus (BLA), the numbers of GABA(A) receptor 2 subunit clusters are reduced. In BLA pyramidal neurons, the frequency of norepinephrine-induced GABAergic inhibitory synaptic currents was reduced markedly in mdx mice. Morpholino oligonucleotide-induced expression of truncated dystrophin in the brains of mdx mice, but not in the muscle, ameliorated the abnormal freezing response to restraint. These results suggest that a deficit of brain dystrophin induces an alteration of amygdala local inhibitory neuronal circuits and enhancement of fear-motivated defensive behaviours in mice.