Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin1A receptors
Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin1A receptors
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DOI：
10.1073/pnas.97.26.14731
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发表时间：
2000-12-19
影响因子：
11.1
通讯作者：
Tóth, M
中科院分区：
文献类型：
--
作者：
Sarnyai, Z;Sibille, EL;Tóth, M
海马是脑干多巴胺能神经元的主要边缘靶点，其通过突触后5-羟色胺（1A）受体（5-HT 1A受体）调节恐惧、焦虑和学习。由于慢性应激选择性下调海马体中的5-HT 1A受体，我们假设缺乏这些受体的小鼠可能表现出异常，让人联想到与应激相关的精神疾病的症状。特别是，海马5-HT 1A受体的缺陷可能导致这些疾病中常见的认知异常。为了测试5-HT 1A受体缺陷是否会损害海马相关功能，我们研究了5-HT 1A敲除（KO）小鼠的海马依赖性学习和记忆、海马突触可塑性和边缘神经元兴奋性。5-HT 1A-KO动物在海马依赖性学习和记忆测试中表现出缺陷，例如Morris水迷宫的隐藏平台（空间）版本和Y迷宫的延迟版本。KO小鼠在非海马记忆任务中的表现并未受损，例如可见平台（非空间）版本的莫里斯水迷宫、立即版本的Y迷宫和工作记忆的自发交替测试。此外，在5-HT 1A-KO小鼠海马齿状回的成对脉冲易化受损。最后，5-HT 1A-KO小鼠，与野生型动物相比，表现出更高的边缘：兴奋性表现为较低的癫痫发作阈值和较高的致死率响应红藻氨酸管理。这些结果表明，5-HT 1A受体是维持正常海马功能所必需的，并暗示了5-HT 1A受体在应激相关疾病中的海马相关症状，如认知障碍中的作用。
The hippocampus is a major limbic target of the brainstem serotonergic neurons that modulate fear, anxiety, and learning through postsynaptic serotonin(1A) receptors (5-HT1A receptors). Because chronic stress selectively down-regulates the 5-HT1A receptors in the hippocampus, we hypothesized that mice lacking these receptors may exhibit abnormalities reminiscent of symptoms of stress-related psychiatric disorders. In particular, a hippocampal deficit in the 5-HT1A receptor could contribute to the cognitive abnormalities often seen in these disorders. To test whether a deficit in 5-HT1A receptors impairs hippocampus-related functions, we studied hippocampal-dependent learning and memory, synaptic plasticity in the hippocampus, and limbic neuronal excitability in 5-HT1A-knockout (KO) mice. 5-HT1A-KO animals showed a deficit in hippocampal-dependent learning and memory tests, such as the hidden platform (spatial) Version of the Morris water maze and the delayed version of the Y maze. The performance of KO mice was not impaired in nonhippocampal memory tasks such as the visible platform (nonspatial) version of the Morris water maze, the immediate version of the Y maze, and the spontaneous-alternation test of working memory. Furthermore, paired-pulse facilitation in the dentate gyrus of the hippocampus was impaired in 5-HT1A-KO mice. Finally, 5-HT1A-KO mice, as compared with wild-type animals, displayed higher limbic: excitability manifested as lower seizure threshold and higher lethality in response to kainic acid administration. These results demonstrate that 5-HT1A receptors are required for maintaining normal hippocampal functions and implicate a role for the 5-HT1A receptor in hippocampal-related symptoms, such as cognitive disturbances, in stress-related disorders.