Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice.
Abnormal social behavior, hyperactivity, impaired remote spatial memory, and increased D1-mediated dopaminergic signaling in neuronal nitric oxide synthase knockout mice.
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DOI：
10.1186/1756-6606-2-19
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发表时间：
2009-06-18
期刊：
影响因子：
3.6
通讯作者：
Miyakawa T
中科院分区：
文献类型：
--
作者：
Tanda K;Nishi A;Matsuo N;Nakanishi K;Yamasaki N;Sugimoto T;Toyama K;Takao K;Miyakawa T
神经元型一氧化氮合酶（nNOS）参与调节脑中多种细胞内信使系统。在人类中，NOS/一氧化氮代谢异常被认为有助于一些神经精神疾病的发病机制和病理生理学，如精神分裂症和双相情感障碍。具有nNOS基因的靶向破坏的小鼠表现出异常行为。在这里，我们对nNOS敲除（KO）小鼠进行了一系列行为测试，以进一步研究nNOS在神经精神功能中的作用。我们还研究了nNOS KO小鼠纹状体切片中nNOS在多巴胺/DARPP-32信号传导中的作用，以及给予多巴胺D1受体激动剂对nNOS KO小鼠行为的影响。nNOS KO小鼠在新的环境中表现出过度运动活动，增加了它们在笼中的社会互动，减少了抑郁相关行为，并损害了空间记忆保持。在nNOS KO小鼠的纹状体切片中，多巴胺D1受体激动剂SKF 81297对DARPP-32和AMPA受体亚基GluR 1在蛋白激酶A位点的磷酸化的作用增强。与生化结果一致，腹膜内注射低剂量SKF 81297显著降低了nNOS KO小鼠的前脉冲抑制，但在野生型小鼠中没有。这些发现表明，nNOS KO上调多巴胺D1受体信号传导，并诱导异常的社会行为，多动和受损的远程空间记忆。nNOS基因敲除小鼠可作为一种独特的精神疾病动物模型。
Neuronal nitric oxide synthase (nNOS) is involved in the regulation of a diverse population of intracellular messenger systems in the brain. In humans, abnormal NOS/nitric oxide metabolism is suggested to contribute to the pathogenesis and pathophysiology of some neuropsychiatric disorders, such as schizophrenia and bipolar disorder. Mice with targeted disruption of the nNOS gene exhibit abnormal behaviors. Here, we subjected nNOS knockout (KO) mice to a battery of behavioral tests to further investigate the role of nNOS in neuropsychiatric functions. We also examined the role of nNOS in dopamine/DARPP-32 signaling in striatal slices from nNOS KO mice and the effects of the administration of a dopamine D1 receptor agonist on behavior in nNOS KO mice. nNOS KO mice showed hyperlocomotor activity in a novel environment, increased social interaction in their home cage, decreased depression-related behavior, and impaired spatial memory retention. In striatal slices from nNOS KO mice, the effects of a dopamine D1 receptor agonist, SKF81297, on the phosphorylation of DARPP-32 and AMPA receptor subunit GluR1 at protein kinase A sites were enhanced. Consistent with the biochemical results, intraperitoneal injection of a low dose of SKF81297 significantly decreased prepulse inhibition in nNOS KO mice, but not in wild-type mice. These findings indicate that nNOS KO upregulates dopamine D1 receptor signaling, and induces abnormal social behavior, hyperactivity and impaired remote spatial memory. nNOS KO mice may serve as a unique animal model of psychiatric disorders.
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DOI：
10.1073/pnas.1432927100
发表时间：
2003-07-22
影响因子：
11.1
作者：
Gerber, DJ;Hall, D;Tonegawa, S
通讯作者：
Tonegawa, S
影响因子：
16.2
作者：
BREDT, DS;GLATT, CE;SNYDER, SH
通讯作者：
SNYDER, SH
DOI：
10.1073/pnas.87.2.682
发表时间：
1990-01-01
影响因子：
11.1
作者：
BREDT, DS;SNYDER, SH
通讯作者：
SNYDER, SH
影响因子：
4.8
作者：
Christopherson, KS;Hillier, BJ;Bredt, DS
通讯作者：
Bredt, DS
影响因子：
3.3
作者：
Bernstein, HG;Stanarius, A;Bogerts, B
通讯作者：
Bogerts, B