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.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine that has a dual role, working both as an autacoid in the periphery and as a neurotransmitter in the brain
TPH1 is mainly expressed in the gut and is responsible for the synthesis of peripheral serotonin, tryptophan hydroxylase 2 (TPH2) is expressed in the neurons of the raphenuclei in the brainstem[2,3,4] and in myenteric neurons in the gut,[5] but not in other peripheral organs such as the lung, heart, kidney or liver.[6,7]
We evaluated the rate of serotonin synthesis in the central nervous system (CNS) of Tph2À/À and Tph2heterozygous (Tph[2] þ /À) mice, and investigated the consequence of complete and partial central serotonin depletion on anxiety, aggression and depression-like behavior
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine that has a dual role, working both as an autacoid in the periphery and as a neurotransmitter in the brain. Synthesis of 5-HT starts with the conversion of the essential amino acid tryptophan (Trp) to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase (TPH). 5-HTP is decarboxylated to 5-HT by the aromatic amino acid decarboxylase. Tph2À/À mice catch up the body weight and at the age of 3 months are not any more distinguishable from wild-type mice. These mice exhibit altered thermoregulation and respiratory control, and impaired maternal care.[8]
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