TY - JOUR

T1 - Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

AU - Beaulieu, Jean Martin

AU - Zhang, Xiaodong

AU - Rodriguiz, Ramona M.

AU - Sotnikova, Tatyana D.

AU - Cools, Michael J.

AU - Wetsel, William C.

AU - Gainetdinov, Raul R.

AU - Caron, Marc G.

PY - 2008/1/29

Y1 - 2008/1/29

N2 - 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.

AB - 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.

KW - Functional polymorphism

KW - GSK-3

KW - Mood disorders

KW - Serotonin

KW - Tph2

UR - http://www.scopus.com/inward/record.url?scp=39549108481&partnerID=8YFLogxK

U2 - 10.1073/pnas.0711496105

DO - 10.1073/pnas.0711496105

M3 - Article

C2 - 18212115

AN - SCOPUS:39549108481

VL - 105

SP - 1333

EP - 1338

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 4

ER -