Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin <sub>1A</sub> receptors

DOI Web Site 被引用文献22件
  • Zoltán Sarnyai
    Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021
  • Etienne L. Sibille
    Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021
  • Constantine Pavlides
    Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021
  • Robert J. Fenster
    Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021
  • Bruce S. McEwen
    Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021
  • Miklós Tóth
    Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10021

説明

<jats:p> The hippocampus is a major limbic target of the brainstem serotonergic neurons that modulate fear, anxiety, and learning through postsynaptic serotonin <jats:sub>1A</jats:sub> receptors (5-HT <jats:sub>1A</jats:sub> receptors). Because chronic stress selectively down-regulates the 5-HT <jats:sub>1A</jats:sub> 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-HT <jats:sub>1A</jats:sub> receptor could contribute to the cognitive abnormalities often seen in these disorders. To test whether a deficit in 5-HT <jats:sub>1A</jats:sub> receptors impairs hippocampus-related functions, we studied hippocampal-dependent learning and memory, synaptic plasticity in the hippocampus, and limbic neuronal excitability in 5-HT <jats:sub>1A</jats:sub> -knockout (KO) mice. 5-HT <jats:sub>1A</jats:sub> -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-HT <jats:sub>1A</jats:sub> -KO mice. Finally, 5-HT <jats:sub>1A</jats:sub> -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-HT <jats:sub>1A</jats:sub> receptors are required for maintaining normal hippocampal functions and implicate a role for the 5-HT <jats:sub>1A</jats:sub> receptor in hippocampal-related symptoms, such as cognitive disturbances, in stress-related disorders. </jats:p>

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