Impaired hippocampal-dependent learning and functional abnormalities in the hippocampus in mice lacking serotonin _1A receptors

Abstract

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-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-HT1A 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-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-HT 1A-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-HT 1A receptor in hippocampal-related symptoms, such as cognitive disturbances, in stress-related disorders.A deficiency of postsynaptic serotonin 1A (5-HT 1A ) has been implicated in mood disorders, such as depression and posttraumatic stress disorder and panic disorder (1-4). In particular, a receptor deficiency has been reproducibly found in the limbic systems of people with mood disorders (3, 5). Decreased 5-HT1A receptor binding was found in the brains of depressed suicide victims (6), and recent brain-imaging studies performed with positron-emission tomography have revealed decreased 5-HT 1A -receptor densities in the medial temporal lobe and other limbic brain regions of patients with major depression (7,8). Also, chronic stress, which is well known to be a major factor in the development of mood disorders, has been shown to lead to a specific down-regulation of 5-HT 1A receptors in the hippocampus of experimental animals (9-15). These results strongly suggest that down-regulation of 5-HT 1A receptors, caused by either genetic or stress-related processes, may significantly contribute to the development of mood disorders in humans. Specifically, a hippocampal deficit in 5-HT 1A receptors could contribute to the cognitive abnormalities often seen in people with mood disorders (16-19).The serotonergic system seems to play a role in behaviors that invo...

IGF‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

“…Mice were required to enter an arm with all four paws in order for it to be counted as an entry. The results are expressed as number of entries (entry) and time spent (dwell) in the novel arm as % of all entries and time spent in novel and other arm (Sarnyai et al ., 2000). Entering the novel arm more frequently and for longer periods of time indicates intact memory and novelty‐seeking behavior because of the innate tendency of mice to explore.…”

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

“…Experimental data suggest that GABA B receptor antagonists display antidepressant-like properties via an interaction with the serotonergic system [43]. 5-HT 1A receptors are found on GABA inhibitory interneurons [52], and GABA A and GABA B receptor activation inhibits the firing of serotonergic neurons in the dorsal raphe nucleus [53]. Also, in 5-HT transporter (5-HTT) knockouts, the GABA B agonist, baclofen, causes lower hyperpolarization and inhibition of neuronal firing of the dorsal raphe nucleus serotonergic neurons [53].…”

“…Studies involving tissue-specific rescue of the 5-HT 1A knockout showed that recovery of the wildtype phenotype required the expression of 5-HT 1A receptors in the hippocampus and cortex, and not in raphe nuclei, during early postnatal development and not during adulthood [73]. Studies carried out to ascertain how chronic stress affects learning and memory mediated via 5-HT 1A receptors, showed that these mice exhibit a deficit in hippocampaldependent learning and memory, impaired paired-pulse facilitation in the dentate gyrus, and higher limbic excitability [52]. This demonstrated the involvement of 5-HT 1A receptors in the decreased cognitive function that is often associated with mood disorders [52].…”

“…Studies carried out to ascertain how chronic stress affects learning and memory mediated via 5-HT 1A receptors, showed that these mice exhibit a deficit in hippocampaldependent learning and memory, impaired paired-pulse facilitation in the dentate gyrus, and higher limbic excitability [52]. This demonstrated the involvement of 5-HT 1A receptors in the decreased cognitive function that is often associated with mood disorders [52].…”

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

“…Finally, we used a two-trial spatial-memory task in a Y maze (20,33,34) to determine whether the reduced neurovascular dysfunction and CAA in Tg2576/CD36 0/0 mice are associated with improved cognitive performance. We chose the Y maze test for its high sensitivity to the behavioral dysfunction of Tg2576 mice (35).…”