Global knockdown of glutamate decarboxylase 67 elicits emotional abnormality in mice.
Global knockdown of glutamate decarboxylase 67 elicits emotional abnormality in mice.
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DOI：
10.1186/s13041-020-00713-2
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发表时间：
2021-01-07
期刊：
影响因子：
3.6
通讯作者：
Yanagawa Y
中科院分区：
文献类型：
--
作者：
Miyata S;Kakizaki T;Fujihara K;Obinata H;Hirano T;Nakai J;Tanaka M;Itohara S;Watanabe M;Tanaka KF;Abe M;Sakimura K;Yanagawa Y
由Gad 1基因编码的谷氨酸脱羧酶67（GAD 67）的表达减少，是在患有几种精神疾病（包括精神分裂症、双相情感障碍和重度抑郁症）的患者死后大脑中的一致发现。GAD 67在大脑中的功能障碍与这些精神疾病的病理生理学有关;然而，GAD 67功能障碍在成熟大脑中的神经生物学后果尚未完全了解，因为纯合Gad 1敲除在新生小鼠中是致命的。我们假设，四环素控制的基因表达/抑制系统可以应用于开发全球GAD 67敲除小鼠，将存活到成年。此外，GAD 67敲除小鼠将为GAD 67功能障碍的神经生物学影响提供新的见解。在这里，我们使用Gad 1STOP −tetO和Gad 1 tTA基因敲入小鼠开发了Gad 1 tTA/STOP−tetO双等位基因敲入小鼠，并将其与Gad 1 +/+小鼠进行了比较。用多西环素（Dox）处理的Gad 1 tTA/STOP-tetO小鼠脑中GAD 67蛋白的表达水平降低了约90%。在Dox处理的Gad 1 tTA/STOP-tetO小鼠的大脑中，GABA含量也降低了。在旷场试验中，Dox处理的Gad 1 tTA/STOP-tetO小鼠表现出过度运动活动和在中心区域停留的时间减少。此外，Dox处理的Gad 1 tTA/STOP-tetO小鼠的声音惊吓反应受损。这些结果表明，GAD 67的整体减少诱发小鼠的情绪异常。这些GAD 67敲除小鼠将有助于阐明情绪异常的神经生物学机制，例如与精神疾病相关的焦虑症状。
Reduced expression of glutamate decarboxylase 67 (GAD67), encoded by the Gad1 gene, is a consistent finding in postmortem brains of patients with several psychiatric disorders, including schizophrenia, bipolar disorder and major depressive disorder. The dysfunction of GAD67 in the brain is implicated in the pathophysiology of these psychiatric disorders; however, the neurobiological consequences of GAD67 dysfunction in mature brains are not fully understood because the homozygous Gad1 knockout is lethal in newborn mice. We hypothesized that the tetracycline-controlled gene expression/suppression system could be applied to develop global GAD67 knockdown mice that would survive into adulthood. In addition, GAD67 knockdown mice would provide new insights into the neurobiological impact of GAD67 dysfunction. Here, we developed Gad1tTA/STOP−tetO biallelic knock-in mice using Gad1STOP−tetO and Gad1tTA knock-in mice, and compared them with Gad1+/+ mice. The expression level of GAD67 protein in brains of Gad1tTA/STOP−tetO mice treated with doxycycline (Dox) was decreased by approximately 90%. The GABA content was also decreased in the brains of Dox-treated Gad1tTA/STOP−tetO mice. In the open-field test, Dox-treated Gad1tTA/STOP−tetO mice exhibited hyper-locomotor activity and decreased duration spent in the center region. In addition, acoustic startle responses were impaired in Dox-treated Gad1tTA/STOP−tetO mice. These results suggest that global reduction in GAD67 elicits emotional abnormalities in mice. These GAD67 knockdown mice will be useful for elucidating the neurobiological mechanisms of emotional abnormalities, such as anxiety symptoms associated with psychiatric disorders.
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影响因子：
4.6
作者：
Magri C;Giacopuzzi E;La Via L;Bonini D;Ravasio V;Elhussiny MEA;Orizio F;Gangemi F;Valsecchi P;Bresciani R;Barbon A;Vita A;Gennarelli M
通讯作者：
Gennarelli M
DOI：
10.1017/s1461145709990587
发表时间：
2010-05
期刊：
The international journal of neuropsychopharmacology
影响因子：
--
作者：
Karolewicz B;Maciag D;O'Dwyer G;Stockmeier CA;Feyissa AM;Rajkowska G
通讯作者：
Rajkowska G
影响因子：
3.6
作者：
Das AT;Tenenbaum L;Berkhout B
通讯作者：
Berkhout B
影响因子：
6.6
作者：
Georgiev, Danko;Yoshihara, Toru;Hashimoto, Takanori
通讯作者：
Hashimoto, Takanori
影响因子：
3.7
作者：
Giacopuzzi E;Gennarelli M;Minelli A;Gardella R;Valsecchi P;Traversa M;Bonvicini C;Vita A;Sacchetti E;Magri C
通讯作者：
Magri C