Ulk2 controls cortical excitatory?inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons
Ulk2 controls cortical excitatory?inhibitory balance via autophagic regulation of p62 and GABAA receptor trafficking in pyramidal neurons
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Ulk2通过自噬调节锥体神经元中p62和GABAA受体运输来控制皮质兴奋性或抑制性平衡
DOI：
10.1093/hmg/ddy219
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发表时间：
2018
影响因子：
3.5
通讯作者：
Sawa Akira
中科院分区：
文献类型：
--
作者：
Sumitomo Akiko;Yukitake Hiroshi;Hirai Kazuko;Horike Kouta;Ueta Keisho;Chung Youjin;Warabi Eiji;Yanagawa Toru;Kitaoka Shiho;Furuyashiki Tomoyuki;Narumiya Shuh;Hirano Tomoo;Niwa Minae;Sibille Etienne;Hikida Takatoshi;Sakurai Takeshi;Ishizuka Koko;Sawa Akira
自噬在包括神经元在内的所有细胞的细胞内降解和维持细胞内稳态中起重要作用。尽管最近的一项研究报道了Ulk 2（启动自噬所必需的基因）的拷贝数变异与精神分裂症（SZ）病例相关，但Ulk 2功能障碍是否是该疾病的病理生理学基础仍有待研究。在这里，我们发现Ulk 2杂合子（Ulk 2 +/−）小鼠上调了一种自噬相关应激反应蛋白-部分原因是锥体神经元中γ-氨基丁酸（GABA）A受体表面表达的选择性下调。在Ulk 2 +/−小鼠中，通过基因降低p62基因剂量或用自噬诱导剂抑制p62蛋白水平，可以恢复GABA A受体表面表达，并挽救行为缺陷。此外，表达一种特异性干扰p62和GABAA受体相关蛋白（一种调节GABAA受体内吞转运的蛋白）相互作用的短肽，也恢复了GABAA受体表面表达，并挽救了Ulk 2 +/−小鼠的行为缺陷。因此，目前的研究揭示了一种新的机制，通过调节锥体神经元中的GABA A受体表面呈递，将失调的自噬与SZ相关的神经系统功能障碍联系起来。
Autophagy plays an essential role in intracellular degradation and maintenance of cellular homeostasis in all cells, including neurons. Although a recent study reported a copy number variation ofUlk2, a gene essential for initiating autophagy, associated with a case of schizophrenia (SZ), it remains to be studied whetherUlk2dysfunction could underlie the pathophysiology of the disease. Here we show thatUlk2heterozygous (Ulk2+/−) mice have upregulated expression of sequestosome-1/p62, an autophagy-associated stress response protein, predominantly in pyramidal neurons of the prefrontal cortex (PFC), and exhibit behavioral deficits associated with the PFC functions, including attenuated sensorimotor gating and impaired cognition.Ulk2+/−neurons showed imbalanced excitatory–inhibitory neurotransmission, due in part to selective down-modulation of gamma-aminobutyric acid (GABA)Areceptor surface expression in pyramidal neurons. Genetically reducingp62gene dosage or suppressing p62 protein levels with an autophagy-inducing agent restored the GABAAreceptor surface expression and rescued the behavioral deficits inUlk2+/−mice. Moreover, expressing a short peptide that specifically interferes with the interaction of p62 and GABAAreceptor-associated protein, a protein that regulates endocytic trafficking of GABAAreceptors, also restored the GABAAreceptor surface expression and rescued the behavioral deficits inUlk2+/−mice. Thus, the current study reveals a novel mechanism linking deregulated autophagy to functional disturbances of the nervous system relevant to SZ, through regulation of GABAAreceptor surface presentation in pyramidal neurons.