Exaggerated aggression and decreased anxiety in mice deficient in brain serotonin

Abstract

Serotonin is a major neurotransmitter in the central nervous system (CNS). Dysregulation of serotonin transmission in the CNS is reported to be related to different psychiatric disorders in humans including depression, impulsive aggression and anxiety disorders. The most frequently prescribed antidepressants and anxiolytics target the serotonergic system. However, these drugs are not effective in 20–30% of cases. The causes of this failure as well as the molecular mechanisms involved in the origin of psychological disorders are poorly understood. Biosynthesis of serotonin in the CNS is initiated by tryptophan hydroxylase 2 (TPH2). In this study, we used Tph2-deficient (Tph2−/−) mice to evaluate the impact of serotonin depletion in the brain on mouse behavior. Tph2−/− mice exhibited increased depression-like behavior in the forced swim test but not in the tail suspension test. In addition, they showed decreased anxiety-like behavior in three different paradigms: elevated plus maze, marble burying and novelty-suppressed feeding tests. These phenotypes were accompanied by strong aggressiveness observed in the resident–intruder paradigm. Despite carrying only one copy of the gene, heterozygous Tph2+/− mice showed only 10% reduction in brain serotonin, which was not sufficient to modulate behavior in the tested paradigms. Our findings provide unequivocal evidence on the pivotal role of central serotonin in anxiety and aggression.

Increased brain-derived neurotrophic factor (BDNF) protein concentrations in mice lacking brain serotonin

“…Both Tph2 -/-and SERT -/-mice have been established on a pure C57BL/6 genetic background [21]. Animals were 10 to 12 weeks old at the time of sacrifice.…”

Mice Genetically Depleted of Brain Serotonin Do Not Display a Depression-like Behavioral Phenotype

“…26 Mosienko and colleagues reported that TPH2 −/− mice displayed increased immobility in the FST but not on the TST. 29 The possibility exists that moderate reductions in brain 5HT, versus the more drastic depletions seen in PET-1 and TPH2 −/− mice, would reveal a depression-like phenotype.…”

“…26 Mosienko and colleagues reported that TPH2 −/− mice displayed increased immobility in the FST but not on the TST. 29 The possibility exists that moderate reductions in brain 5HT, versus the more drastic depletions seen in PET-1 and TPH2 −/− mice, would reveal a depression-like phenotype.Testing of this possibility has been done using mice with partial reductions in TPH2 expression. For instance, Beaulieu and colleagues 47 generated a knockin mouse line that Zhang and colleagues 51 reported a functional single nucleotide polymorphism in the mouse TPH2 gene.…”

“…19,20,[23][24][25][26][27][28] In the course of characterizing the behavioral phenotype of the TPH2 −/− mouse, we and others have noted numerous interesting and novel aspects of 5HT-behavioral relations. TPH2 −/− mice display intense impulsive and compulsive behaviors and extreme aggressiveness, 23,29 as well as autistic-like behavioral traits. 30 Surprisingly, these mice show decreased anxietylike behaviors by comparison to wild-type control mice.…”

The role of serotonin in adult hippocampal neurogenesis

“…Serotonin depletion in transgenic mouse models also results in altered behavior such as exaggerated aggressiveness that goes along with reduced anxiety (Mosienko et al, 2012) and increased impulsivity (Angoa-Perez et al, 2012 Gaspar, 2012, Mosienko et al, 2014); that may reflect unchanged baseline neurogenesis, but also indicates an uncoupling of the behavioral mechanisms governing depression and serotonin levels in a unique homeostasis created over time. Compensatory mechanisms seem to occur in life-long serotonin depletion and the replacement of this neurotransmitter by expression or activity of other neurotransmitter systems has been debated (Beckman and Santos, 2013).…”