Effect of Tryptophan Hydroxylase-2 Gene Variants on Suicide Risk in Major Depression

Lara, Catalina Lopez de; Brezo, Jelena; Rouleau, Guy A.; Lesage, Alain; Dumont, M; Alda, Martin; Benkelfat, Chawki; Turecki, Gustavo

doi:10.1016/j.biopsych.2006.09.008

Cited by 85 publications

(50 citation statements)

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“…Although further genetic studies will be needed to firmly link this functional R441H Tph2 polymorphism with human depres- sion (34,35), large-scale genetic analyses have associated several noncoding polymorphisms in the human TPH2 gene with depression, bipolar disorder, and suicidality (36)(37)(38)(39)(40)(41). Furthermore, several naturally occurring functional polymorphisms in the Tph2 gene have also been identified in mice (15), rhesus monkeys (42), chimpanzees (43), and humans (17)(18)(19).…”

Section: Discussionmentioning

confidence: 99%

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Beaulieu¹,

Zhang²,

Rodriguiz

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

337

317

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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...

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Section: Discussionmentioning

confidence: 99%

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Beaulieu¹,

Zhang²,

Rodriguiz

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

337

317

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“…Although earlier studies reported significant associations between several TPH2 SNPs and both depression and suicidal behavior (Haghighi et al, 2008;Ke et al, 2006;Lopez de Lara et al, 2007;Van Den Bogaert et al, 2006;Zhou et al, 2005;Zill et al, 2004a, b) more recent studies failed to confirm these findings (De Luca et al, 2006;Mann et al, 2008;Zill et al, 2007). Among functionally characterized TPH2 polymorphisms only a few (including G1463A) result in a clear reduction in enzymatic activity, whereas other polymorphisms have only a minor effect on TPH2 activity (McKinney et al, 2009).…”

Section: Human Tph2 Polymorphismsmentioning

confidence: 98%

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

Berger

Weber

Perreau-Lenz

et al. 2012

Neuropsychopharmacol

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The association of single-nucleotide polymorphisms (SNPs) in the human tryptophan hydroxylase 2 (TPH2) gene with anxiety traits and depression has been inconclusive. Observed inconsistencies might result from the fact that TPH2 polymorphisms have been studied in a genetically heterogeneous human population. A defined genetic background, control over environmental factors, and the ability to analyze the molecular and neurochemical consequences of introduced genetic alterations constitute major advantages of investigating SNPs in inbred laboratory mouse strains. To investigate the behavioral and neurochemical consequences of a functional C1473G SNP in the mouse Tph2 gene, we generated congenic C57BL/6N mice homozygous for the Tph2 1473G allele. The Arg 447 substitution in the TPH2 enzyme resulted in a significant reduction of the brain serotonin (5-HT) in vivo synthesis rate. Despite decreased 5-HT synthesis, we could detect neither a reduction of brain region-specific 5-HT concentrations nor changes in baseline and stress-induced 5-HT release using a microdialysis approach. However, using a [ 35 S]GTP-g-S binding assay and 5-HT 1A receptor autoradiography, a functional desensitization of 5-HT 1A autoreceptors could be identified. Furthermore, behavioral analysis revealed a distinct anxiety phenotype in homozygous Tph2 1473G mice, which could be reversed with chronic escitalopram treatment. Alterations in depressive-like behavior could not be detected under baseline conditions or after chronic mild stress. These findings provide evidence for an involvement of functional Tph2 polymorphisms in anxiety-related behaviors, which are likely not caused directly by alterations in 5-HT content or release but are rather due to compensatory changes during development involving functional desensitization of 5-HT 1A autoreceptors.

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“…Some haplotype studies suggest association of the TPH2 gene to major depression (Zill et al, 2004a;Van Den Bogaert et al, 2006;Zhou et al, 2005), suicide (Zill et al, 2004c), suicide attempt (Zhou et al, 2005;de Lara et al, 2007), and bipolar disorder (Lopez et al, 2007;Harvey et al, 2004;Van Den Bogaert et al, 2006), and others disagree (De Luca et al, 2004, 2005b.…”

Section: Introductionmentioning

confidence: 99%