Role of GSK3 beta in behavioral abnormalities induced by serotonin deficiency.
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.
Beaulieu
Jean-Martin
JM
Department of Cell Biology, Mouse Behavioral and Neuroendocrine Analyses Core Facility, Duke University Medical Center, Durham, NC 27710, USA.
Zhang
Xiaodong
X
Rodriguiz
Ramona M
RM
Sotnikova
Tatyana D
TD
Cools
Michael J
MJ
Wetsel
William C
WC
Gainetdinov
Raul R
RR
Caron
Marc G
MG
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007103:Immobilization / Q000502:physiology; D007398:Interpersonal Relations; D008124:Locomotion / Q000235:genetics / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016297:Mutagenesis, Site-Directed; D012701:Serotonin / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics; D014365:Tryptophan Hydroxylase / Q000235:genetics / Q000502:physiology
D012701:Serotonin; C487802:Tph2 protein, mouse; D014365:Tryptophan Hydroxylase; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3