Glucogen Synthase Kinase 3beta and Bipolar Disorder

Summary

Principal Investigator: Xiaohua Li
Abstract: DESCRIPTION (provided by applicant): This project will study the regulation of glycogen synthase kinase 3beta, its modulation by mood stabilizers and its potential role in bipolar disorder. The five-year plans to enable the candidate to develop into an independent psychiatric investigator to conduct translational research in bipolar disorder. The project provides extensive training in new research skills, including studying transcription factors and gene expression, using gene microarray techniques, and conducting clinical research. The central hypothesis for the research is that abnormal functioning of GSK3beta plays a role in the development of bipolar disorder. The hypothesis is based on the recent evidence that bipolar disorder may involve impaired neural plasticity and neural degeneration, and GSK3beta, a protein kinase with multiple regulatory functions in neuronal tissues, is a major intracellular target of the mood stabilizer lithium. Our preliminary results also indicate that three mood stabilizers have modulatory effects on GSK3beta. Three Specific Aims will be pursued to test the central hypothesis and accomplish the overall objective of this application. Specific Aim 1 will determine the role of GSK3beta in the brain-derived neurotrophic factor (BDNF)-induced cyclic AMP responsive element binding protein (CREB) transcription factor activity and its modulation by mood stabilizers. BDNF-mediated signaling and CREB will be studied because they are components of a neural-specific signaling system that appears to be impaired in mood disorders. Specific Aim 2 will determine the role of GSK3beta in BDNF-induced gene expression and its modulation by mood stabilizers. Gene expression will be studied because it is thought to be impaired in bipolar disorder and is modified by treatment with mood stabilizers. This hypothesis will be tested by measuring gene expression using gene microarray. The Specific Aims 1 and 2 provide training in studies of regulation of transcription factors and gene expression to obtain new skills in molecular biology, which is an important training component of this application. Specific Aim 3 will measure GSK3beta activity in peripheral blood lymphocytes of patients with bipolar disorder before and after treatment with lithium. This Specific Aim has a clinical research component to bridge the clinical and basic studies, and to facilitate the candidate's development of skills in translational research. The proposed research is innovative, because it will identify the role of GSK3beta in the development of bipolar disorder. The proposed research is expected to have a significant impact on understanding the pathophysiology and improving the treatment of bipolar disorder. At the completion of these studies, the candidate will have established a solid background in molecular biology techniques and clinical research enabling her to be an independent psychiatric researcher who possesses the ability to use molecular biology techniques to answer clinical questions.
Funding Period: 2003-04-01 - 2009-03-31
more information: NIH RePORT

Top Publications

  1. pmc Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances
    Abigail Polter
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Neuropsychopharmacology 35:1761-74. 2010
  2. pmc Functional significance of glycogen synthase kinase-3 regulation by serotonin
    Abigail M Polter
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
    Cell Signal 24:265-71. 2012
  3. ncbi Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics
    Xiaohua Li
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Int J Neuropsychopharmacol 10:7-19. 2007
  4. pmc Lithium regulates glycogen synthase kinase-3beta in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder
    Xiaohua Li
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Biol Psychiatry 61:216-22. 2007
  5. ncbi Lithium reduces FoxO3a transcriptional activity by decreasing its intracellular content
    Zhengquan Mao
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294 0017, USA
    Biol Psychiatry 62:1423-30. 2007
  6. ncbi Efficacy of risperidone augmentation to antidepressants in the management of suicidality in major depressive disorder: a randomized, double-blind, placebo-controlled pilot study
    Hollis Reeves
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, AL 35294, USA
    J Clin Psychiatry 69:1228-336. 2008
  7. pmc Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation
    Abigail Polter
    Department of Psychiatry, University of Alabama at Birmingham, 1075 Sparks Center, 1720 7th Avenue South, Birmingham, AL35294 0017, USA
    Biol Psychiatry 65:150-9. 2009
  8. pmc Regulation of serotonin 1B receptor by glycogen synthase kinase-3
    Ligong Chen
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Mol Pharmacol 76:1150-61. 2009

Scientific Experts

  • Xiaohua Li
  • Abigail Polter
  • Sufen Yang
  • Richard S Jope
  • Abigail M Polter
  • Ligong Chen
  • Hollis Reeves
  • Rusheng Zhang
  • Zhengquan Mao
  • J David Sweatt
  • Ling Song
  • Lori McMahon
  • Courtney A Miller
  • Alfred A Bartolucci
  • Eleonore Beurel
  • Rakesha Garner
  • Thomas van Groen
  • Gregory D Salinas
  • Ronald A Depinho
  • Stanford L Peng
  • Anna A Zmijewska
  • Ji Hye Paik
  • Sachin Batra
  • Daniel C Dahl
  • Roberta S May
  • Liqin Liu

Detail Information

Publications8

  1. pmc Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances
    Abigail Polter
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Neuropsychopharmacology 35:1761-74. 2010
    ....
  2. pmc Functional significance of glycogen synthase kinase-3 regulation by serotonin
    Abigail M Polter
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
    Cell Signal 24:265-71. 2012
    ....
  3. ncbi Regulation of mouse brain glycogen synthase kinase-3 by atypical antipsychotics
    Xiaohua Li
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Int J Neuropsychopharmacol 10:7-19. 2007
    ..These findings may support the pharmacological mechanisms of atypical antipsychotics in the treatment of mood disorders...
  4. pmc Lithium regulates glycogen synthase kinase-3beta in human peripheral blood mononuclear cells: implication in the treatment of bipolar disorder
    Xiaohua Li
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294 0017, USA
    Biol Psychiatry 61:216-22. 2007
    ..We tested whether lithium modified GSK3beta in vivo or in vitro in peripheral blood mononuclear cells (PBMCs) from healthy control and bipolar disorder subjects...
  5. ncbi Lithium reduces FoxO3a transcriptional activity by decreasing its intracellular content
    Zhengquan Mao
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294 0017, USA
    Biol Psychiatry 62:1423-30. 2007
    ..Searching for therapeutic targets downstream of BDNF signaling will facilitate the development of new treatment approaches for mood disorders...
  6. ncbi Efficacy of risperidone augmentation to antidepressants in the management of suicidality in major depressive disorder: a randomized, double-blind, placebo-controlled pilot study
    Hollis Reeves
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, AL 35294, USA
    J Clin Psychiatry 69:1228-336. 2008
    ..This pilot study was designed to investigate the efficacy of risperidone augmentation to antidepressants in the acute management of suicidality and other core symptoms in MDD with suicidality...
  7. pmc Forkhead box, class O transcription factors in brain: regulation and behavioral manifestation
    Abigail Polter
    Department of Psychiatry, University of Alabama at Birmingham, 1075 Sparks Center, 1720 7th Avenue South, Birmingham, AL35294 0017, USA
    Biol Psychiatry 65:150-9. 2009
    ..Here, we investigated whether brain FoxO1 and FoxO3a can be regulated by serotonin and antidepressant treatment and whether their genetic deletion affects behaviors...
  8. pmc Regulation of serotonin 1B receptor by glycogen synthase kinase-3
    Ligong Chen
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Mol Pharmacol 76:1150-61. 2009
    ....