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

Abstract

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.

Gut-Brain Axis: Probiotic,Bacillus subtilis, Prevents Aggression via the Modification of the Central Serotonergic System

“…In GF mice, gut microbiota also modulates the 5-HT synthesis and release at both the brain and peripheral levels directly and indirectly via the microbiota-host interactions [148]. Reduced 5-HT activity (a 5-HT deficiency) has been associated with personality traits (interspecific social behavior), such as impulsivity and aggression, and deteriorated stress coping capability (increased stress response) in humans and various animals [149,150] including chickens [24,[151][152][153][154].…”

“…Hypothalamic injection of a 5-HT1a agonist inhibits aggression in male hamsters [174]. Depletion of brain 5-HT in TPH2 mutant mice marks aggression and lowers habituation in novel environments [149]. In addition, 5-HT1BR knockout mice show increased aggression and impulsivity [175,176].…”

Ablation of Ventral Midbrain/Pons GABA Neurons Induces Mania-like Behaviors with Altered Sleep Homeostasis and Dopamine D2R-mediated Sleep Reduction

“…Serotonin (5-HT) is also involved in regulating both sleep/wake and locomotor activity (Correia et al, 2017;Saper et al, 2005). Studies in both humans and mice suggest that serotonin is involved in mania and its treatment (Maddaloni et al, 2018;Shiah and Yatham, 2000). In this sense, investigating the loss of VMP GABAergic innervation to DRN serotonergic neurons is another potential study direction.…”

TRPM3 in Brain (Patho)Physiology

“…This suggestion was based on the facts that the PregS level-regulating steroid sulfatase (STS) enzyme deficiency is positively linked to mental health conditions and depression in human patients (Cavenagh et al, 2019) and PregS levels were reportedly increased in STS-deficient patients (Sánchez-Guijo et al, 2016). Fittingly, it was also shown that TRPM3 expression was altered in a mouse model of bipolar disorder due to serotonin depletion (Maddaloni et al, 2018), thereby supporting the idea that TRPM3 may regulate mood conditions. However, no hard evidence was provided yet for the mechanistic involvement of TRPM3 in the development and/or manifestation of the abovestudied diseases.…”