Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Departments of *Cell Biology,
^‖Medicine,
^¶Neurobiology, and
^§Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analyses Core Facility, Duke University Medical Center, Durham, NC 27710

Communicated by L. L. Iversen, University of Oxford, Oxford, United Kingdom, December 6, 2007 (received for review November 6, 2007)

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 (≈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 3β (GSK3β), a signaling molecule modulated by many psychiatric therapeutic agents. Importantly, inactivation of GSK3β 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 GSK3β signaling as an important pathway through which brain 5-HT deficiency induces abnormal behaviors. Targeting GSK3β and related signaling events may afford therapeutic advantages for the management of certain 5-HT-related psychiatric conditions.

Footnotes

**To whom correspondence should be addressed. E-mail: m.caron{at}cellbio.duke.edu
Author contributions: J.-M.B. and X.Z. contributed equally to this work; J.-M.B., X.Z., R.M.R., W.C.W., R.R.G., and M.G.C. designed research; J.-M.B., X.Z., R.M.R., T.D.S., M.J.C., and R.R.G. performed research; J.-M.B., X.Z., R.M.R., T.D.S., and R.R.G. analyzed data; and J.-M.B., X.Z., W.C.W., R.R.G., and M.G.C. wrote the paper.
↵ ^†Present address: CRULRG, Research Institute, Université Laval, Québec City, Canada.
↵ ^‡Present address: Duke–National University of Singapore Graduate Medical School, Singapore.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0711496105/DC1.