Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin(1A) receptors

The hippocampus is a major limbic target of the brainstem serotonergic neur ons that modulate fear, anxiety, and learning through postsynaptic serotoni n(1A) receptors (5-HT1A receptors). Because chronic stress selectively down -regulates the 5-HT1A receptors in the hippocampus, we hypothesized that mi ce lacking these receptors may exhibit abnormalities reminiscent of symptom s of stress-related psychiatric disorders. In particular, a hippocampal def icit in the 5-HT1A receptor could contribute to the cognitive abnormalities often seen in these disorders. To test whether a deficit in 5-HT1A recepto rs impairs hippocampus-related functions, we studied hippocampal-dependent learning and memory, synaptic plasticity in the hippocampus, and limbic neu ronal excitability in 5-HT1A-knockout (KO) mice. 5-HT1A-KO animals showed a deficit in hippocampal-dependent learning and memory tests, such as the hi dden platform (spatial) Version of the Morris water maze and the delayed ve rsion of the Y maze. The performance of KO mice was not impaired in nonhipp ocampal memory tasks such as the visible platform (nonspatial) version of t he Morris water maze, the immediate version of the Y maze, and the spontane ous-alternation test of working memory. Furthermore, paired-pulse facilitat ion 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 hig her limbic: excitability manifested as lower seizure threshold and higher l ethality in response to kainic acid administration. These results demonstra te that 5-HT1A receptors are required for maintaining normal hippocampal fu nctions and implicate a role for the 5-HT1A receptor in hippocampal-related symptoms, such as cognitive disturbances, in stress-related disorders.