Role of GSK3beta in behavioral abnormalities induced by serotonin deficiency.

Role of GSK3beta in behavioral abnormalities induced by serotonin deficiency. Research Abstract Details 

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Role of GSK3beta in behavioral abnormalities induced by serotonin deficiency. Abstract Text:

Jean-Martin Beaulieu,Xiaodong Zhang,Ramona M Rodriguiz,Tatyana D Sotnikova,Michael J Cools,William C Wetsel,Raul R Gainetdinov,Marc G Caron,

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 ( approximately 80%) 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 3beta (GSK3beta), a signaling molecule modulated by many psychiatric therapeutic agents. Importantly, inactivation of GSK3beta 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 GSK3beta signaling as an important pathway through which brain 5-HT deficiency induces abnormal behaviors. Targeting GSK3beta and related signaling events may afford therapeutic advantages for the management of certain 5-HT-related psychiatric conditions.

Role of GSK3beta in behavioral abnormalities induced by serotonin deficiency. Publishing Authors By Initials

JM Beaulieu,X Zhang,RM Rodriguiz,TD Sotnikova,MJ Cools,WC Wetsel,RR Gainetdinov,MG Caron,

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Role of GSK3beta in behavioral abnormalities induced by serotonin deficiency. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Proceedings of the National Academy of Sciences of

VOLUME: 105

Page Numbers: 1333-8

Journal Abbreviation: Proc. Natl. Acad. Sci. U.S.A.

ISSN: 1091-6490

DAY: 22

MONTH: 01

YEAR: 2008

Role of GSK3beta in behavioral abnormalities induced by serotonin deficiency. Information

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LANGUAGE: eng

NlmUniqueID: 7505876

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Grant and Affiliation Information for Role of GSK3beta in behavioral abnormalities induced by serotonin deficiency.

AFFILIATION: Department of Cell Biology, Mouse Behavioral and Neuroendocrine Analyses Core Facility, Duke University Medical Center, Durham, NC 27710, USA.

Country: United States

AGENCY: United States NINDS

GRANT: NS19576

ACRONYM: NS

MEDLINETA: Proc Natl Acad Sci U S A

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