期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2008
卷号：105
期号：4
页码：1333-1338
DOI：10.1073/pnas.0711496105
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：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 ({approx}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 3{beta} (GSK3{beta}), a signaling molecule modulated by many psychiatric therapeutic agents. Importantly, inactivation of GSK3{beta} 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{beta} signaling as an important pathway through which brain 5-HT deficiency induces abnormal behaviors. Targeting GSK3{beta} and related signaling events may afford therapeutic advantages for the management of certain 5-HT-related psychiatric conditions.
