Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Abstract

Dysregulation of brain serotonin (5-HT) neurotransmission is thought to underlie mental conditions as diverse as depression, anxiety disorders, bipolar disorder, autism, and schizophrenia. Despite treatment of these conditions with serotonergic drugs, the molecular mechanisms by which 5-HT is involved in the regulation of aberrant emotional behaviors are poorly understood. Here, we generated knockin mice expressing a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2 (Tph2). This mutant is equivalent to a rare human variant (R441H) identified in few individuals with unipolar major depression. Expression of mutant Tph2 in mice results in markedly reduced (Ϸ80%) brain 5-HT production and leads to behavioral abnormalities in tests assessing 5-HT-mediated emotional states. This reduction in brain 5-HT levels is accompanied by activation of glycogen synthase kinase 3␤ (GSK3␤), a signaling molecule modulated by many psychiatric therapeutic agents. Importantly, inactivation of GSK3␤ in Tph2 knockin mice, using pharmacological or genetic approaches, alleviates the aberrant behaviors produced by 5-HT deficiency. These findings establish a critical role of Tph2 in the maintenance of brain serotonin homeostasis and identify GSK3␤ signaling as an important pathway through which brain 5-HT deficiency induces abnormal behaviors. Targeting GSK3␤ and related signaling events may afford therapeutic advantages for the management of certain 5-HT-related psychiatric conditions. GSK-3 ͉ mood disorders ͉ serotonin ͉ Tph2 ͉ functional polymorphism S erotonin (5-HT) is involved in multiple aspects of normal brain functions ranging from the regulation of mood to the control of appetite and social interactions (1-3). Several studies have suggested a contribution of abnormal 5-HT transmission in various human psychiatric conditions and drugs acting on 5-HT neurotransmission are commonly used for the management of major depression, anxiety disorder, obsessive-compulsive disorder, autism, and schizophrenia (1-3). Although drugs that influence the 5-HT system can affect histone acetylation, modulate production of brain-derived neurotrophic factor, increase neural progenitor cell proliferation, and inhibit glycogen synthase kinase 3␤ (GSK3␤) in certain brain areas (4, 5), the mechanisms underlying the regulation of behavior by 5-HT are still obscure.There are indications that pharmacologic manipulations of 5-HT levels by different classes of drugs can affect distinct neuronal signaling mechanisms (6-9). For instance, multiple classes of 5-HT drugs, including selective 5-HT reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors, and atypical antipsychotics (5, 7, 9), inhibit brain GSK3␤ signaling. GSK3␤ is also inhibited in vivo by lithium (6, 10-12), which is often used in combination with antidepressants for the management of certain mood disorders (13). However, whether these changes in GSK3␤ are incidental or contribute to the regulation of 5-HT-related abnormal behaviors is unexplored (5...

A Functional Tph2 C1473G Polymorphism Causes an Anxiety Phenotype via Compensatory Changes in the Serotonergic System

“…Most relevant to our study are results from their heterozygous 1449A mice, in which 5-HT synthesis was only reduced by 40% (Beaulieu et al, 2008). This decrease is comparable to the reduction of 5-HT synthesis detected in our 1473G/G mice.…”

“…We demonstrate that 1473G/G mice show a distinct anxiety phenotype, which could be observed in four different anxiety tests. A rare human G1463A TPH2 SNP was analyzed via a knock-in approach in transgenic mice (Beaulieu et al, 2008;Jacobsen et al, 2011). Mice homozygous for the corresponding mouse Tph2 allele 1449A showed an 80% reduction of 5-HT synthesis and a strong decrease in total and extracellular 5-HT concentrations.…”

“…This can either be achieved by a knock-in strategy in embryonic stem cells (Beaulieu et al, 2008) or alternatively by generating congenic strains by a backcrossing strategy in which one inbred strain is mated to another recipient inbred strain (Tenner et al, 2008). A 'knock-in' approach was applied to study the consequences of the human TPH2 SNP G1463A (Beaulieu et al, 2008), which previously had been shown to be associated with unipolar depressive disorder (Zhang et al, 2005). The respective polymorphism (G1449A) in the mouse Tph2 gene reduced the enzymatic activity of TPH2 by 80% and led to a highly significant reduction of extracellular 5-HT concentration in several brain regions (Jacobsen et al, 2011).…”

“…With this approach, a comparative functional analysis of a specific SNP on an identical genetic background is feasible. This can either be achieved by a knock-in strategy in embryonic stem cells (Beaulieu et al, 2008) or alternatively by generating congenic strains by a backcrossing strategy in which one inbred strain is mated to another recipient inbred strain (Tenner et al, 2008). A 'knock-in' approach was applied to study the consequences of the human TPH2 SNP G1463A (Beaulieu et al, 2008), which previously had been shown to be associated with unipolar depressive disorder (Zhang et al, 2005).…”

Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour

“…Chronic unpredictable stress further aggravates these traits. The impulsive and hyperaggressive behaviour of Tph2 2/2 mice resembles the increased defensiveness reported for Pet1 KO [17] and Tph2 R439H mutants [19]. Acute treatment with 5-HT 1A and 5-HT 1B receptor agonists (or 5-HT 2A/2C antagonists) via their inhibitory action on neurotransmission (pre-synaptically or post-synaptically) was reported to reduce aggressive behaviour, and it was suggested that low 5-HT levels in the brain are associated with maladaptive forms of excessive violence rather than with natural defensiveness [3].…”