Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin 1A receptors
Open accessAbstract
The hippocampus is a major limbic target of the brainstem serotonergic neurons that modulate fear, anxiety, and learning through postsynaptic serotonin 1A receptors (5-HT 1A receptors). Because chronic stress selectively down-regulates the 5-HT 1A 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 1A receptor could contribute to the cognitive abnormalities often seen in these disorders. To test whether a deficit in 5-HT 1A receptors impairs hippocampus-related functions, we studied hippocampal-dependent learning and memory, synaptic plasticity in the hippocampus, and limbic neuronal excitability in 5-HT 1A -knockout (KO) mice. 5-HT 1A -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 1A -KO mice. Finally, 5-HT 1A -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 1A receptors are required for maintaining normal hippocampal functions and implicate a role for the 5-HT 1A receptor in hippocampal-related symptoms, such as cognitive disturbances, in stress-related disorders.
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The Y-maze test was conducted according to established laboratory protocols.
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- Authors
- Sarnyai, Z., Sibille, E. L., Pavlides, C., Fenster, R. J., McEwen, B. S., & Tóth, M.
- Affiliations
- 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
- Cornell University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2000-12-19
- Volume
- 97
- Issue
- 26
- Pages
- 14731-14736
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC18987
- OpenAlex
- W2069474577
- Cited by
- 396
- References
- 5
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 20 · 2023: 22 · 2022: 25 · 2021: 27 · 2020: 25 · 2019: 20 · 2018: 17 · 2017: 11 · 2016: 15 · 2015: 15 · 2014: 19 · 2013: 14 · 2012: 13
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ResearchOnline - JCU (James Cook University) (submittedVersion)
- Funders
- National Institute of Mental Health (MH-41256, R37MH041256, R01MH058669, R01MH041256, MH58669)
- National Institute of Neurological Disorders and Stroke (R01NS034151, NS34151)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- 5-HT1A receptor, hippocampus-dependent learning, spatial memory, synaptic plasticity, paired-pulse facilitation, dentate gyrus, seizure threshold, kainic acid, stress-related psychiatric disorders, chronic stress, cognitive impairment
- MeSH terms
- Animals, Female, Hippocampus, Kainic Acid, Learning, Male, Memory, Receptors, Serotonin, Seizures, Long-Term Potentiation, Mice, Knockout, Receptors, Serotonin, 5-HT1, Mice
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