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Abnormal hippocampal neural plasticity has been implicated in behavioural abnormalities and complex neuropsychiatric conditions, including bipolar disorder (BD). However, the determinants of this neural alteration remain unknown. This work tests the hypothesis that the neurotransmitter serotonin (5-HT) is a key determinant of hippocampal neuroplasticity, and its absence leads to maladaptive behaviour relevant for BD. Depletion of brain 5-HT in  Tph2  mutant mice resulted in reduced behavioural despair, reduced anxiety, marked aggression and lower habituation in novel environments, reminiscent of bipolar-associated manic behaviour. Treatment with valproate produced a substantial improvement of the mania-like behavioural phenotypes displayed by  Tph2  mutants. Brain-wide fMRI mapping in mutants revealed functional hippocampal hyperactivity in which we also observed dramatically increased neuroplasticity. Importantly, remarkable correspondence between the transcriptomic profile of the  Tph2  mutant hippocampus and neurons from bipolar disorder patients was observed. Chronic stress reversed the emotional phenotype and the hippocampal transcriptional landscape of  Tph2  mutants. These changes were associated with inappropriate activation of transcriptional adaptive response to stress as assessed by gene set enrichment analyses in the hippocampus of  Tph2  mutant mice. These findings delineate 5-HT as a critical determinant in BD associated maladaptive emotional responses and aberrant hippocampal neuroplasticity, and support the use of  Tph2 −/− mice as a new research tool for mechanistic and therapeutic research in bipolar disorder.

Serotonin depletion causes valproate-responsive manic-like condition and increased hippocampal neuroplasticity that are reversed by stress