Cited by 368Neurotransmitter Receptor Influence on BehaviorTreatment of Major DepressionTryptophan and brain disorders

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

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Beaulieu, Jean-Martin, Zhang, Xiaodong, Rodriguiz, Ramona M., Sotnikova, Tatyana D., Cools, Michael J., Wetsel, William C., Gainetdinov, Raul R., Caron, Marc G.·2008·Proceedings of the National Academy of Sciences

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 ( 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.

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  • The relationship between the psychopathological features of the illness and its lifetime development is influenced by polymorphisms in the promoter region of the 5-HT transporter gene.

    “Furthermore, the relationship between the psychopathological features of the illness and its lifetime development is also influenced by polymorphisms in the promoter region of the 5-HT transporter gene (Beaulieu et al., 2008; Benedetti et al., 2003; Benedetti et al., 1999)”

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Authors
Beaulieu, J.-M., Zhang, X., Rodriguiz, R. M., Sotnikova, T. D., Cools, M. J., Wetsel, W. C., Gainetdinov, R. R., & Caron, M. G.
Affiliations
  • Departments of *Cell Biology,
  • Duke University (US)
Venue
Proceedings of the National Academy of Sciences
Published
2008-01-29
Volume
105
Issue
4
Pages
1333-1338
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
OpenAlex
W1995120027
Cited by
368
References
52
Citations by year
2026: 10 · 2025: 7 · 2024: 8 · 2023: 10 · 2022: 9 · 2021: 16 · 2020: 13 · 2019: 12 · 2018: 13 · 2017: 14 · 2016: 14 · 2015: 28 · 2014: 34 · 2013: 35 · 2012: 31
FWCI
16.43
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • National University of Singapore (submittedVersion)
Funders
  • National Institute of Mental Health (MH-79201, R01MH079201, MH60451, R01MH073853, MH-73853, R37MH073853, P50MH060451)
  • National Institute of Neurological Disorders and Stroke (NS-19576, R01NS019576)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
glycogen synthase kinase-3β, serotonin deficiency, tryptophan hydroxylase 2, serotonin synthesis, emotional behavior, depression, mental illness, GSK3β signaling, serotonin homeostasis, knock-in mice
MeSH terms
Glycogen Synthase Kinase 3 beta, Animals, Behavior, Animal, Cell Line, Humans, Immobilization, Interpersonal Relations, Locomotion, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Mutant Strains, Serotonin, Tryptophan Hydroxylase, Signal Transduction, Mutagenesis, Site-Directed, Amino Acid Substitution, Glycogen Synthase Kinase 3, Mice

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