GSK3: Neural Modulators and Mood Disorders

Summary

Principal Investigator: Xiaohua Li
Abstract: Mood disorders, including bipolar disorder and depressive disorder, are severe mental illnesses that directly affect over 20% of individuals in the U.S. The pathophysiology of mood disorders is poorly understood, and the treatment options are therefore limited. The long term goal of our research is to understand the pathophysiology and improve the treatment of mood disorders. The objective of this application is to identify a central molecular target in animal brain that is regulated by neural modulators relevant to mood disorders. Based on the accumulating evidence showing that glycogen synthase kinase-3 (GSK3) is an active and highly regulated protein kinase in neural tissues, GSK3 is an intracellular target of neurotrophins involved in mood disorders, the mood stabilizer lithium inhibits GSK3, and we have recently discovered that serotonin, a major mood disorder-related monoamine neurotransmitter, regulates GSK3 in animal brain, we hypothesize that GSK3 is a major protein kinase which activity can be altered by various neural modulators involved in the development and the treatment of mood disorders. Three specific aims will be pursued to test the central hypothesis: Specific Aim 1 will test the hypothesis that mood stabilizing agents, including lithium, divalproate, and lamotrigine, regulate GSK3 in mouse brain through different mechanisms of action. Specific Aim 2 will test the hypothesis that serotonergic modulators used in mood disorders, including serotonin reuptake inhibitor antidepressants and dual-acting antipsychotics, regulate GSK3 in mouse brain. Specific Aim 3 will test the hypothesis that GSK3 activity is abnormally regulated by altered brain activities that simulate what occur in mood disorders, which can be prevented or reversed by mood disorder treatments. These studies will thus use straightforward strategies to conduct clinically relevant research in mood disorders. The proposed research is innovative because it aims to identify the in vivo regulation of GSK3 by various neural modulators relevant to the development and the treatment of mood disorders, which have not to date been thoroughly investigated. This research is expected to provide significant new insight into the pathophysiology and the treatment of mood disorders.
Funding Period: 2006-03-01 - 2011-02-28
more information: NIH RePORT

Top Publications

  1. pmc Regulation of glycogen synthase kinase-3 during bipolar mania treatment
    Xiaohong Li
    Beijing Anding Hospital, Capital Medical University, 1720 Seventh Avenue South, Beijing, China
    Bipolar Disord 12:741-52. 2010
  2. pmc Behavioral stress-induced activation of FoxO3a in the cerebral cortex of mice
    Wenjun Zhou
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294, USA
    Biol Psychiatry 71:583-92. 2012
  3. 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
  4. pmc Glycogen synthase kinase-3β is a functional modulator of serotonin-1B receptors
    L Chen
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Mol Pharmacol 79:974-86. 2011
  5. pmc Is glycogen synthase kinase-3 a central modulator in mood regulation?
    Xiaohua Li
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Neuropsychopharmacology 35:2143-54. 2010
  6. pmc 5-HT1A receptor-regulated signal transduction pathways in brain
    Abigail M Polter
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
    Cell Signal 22:1406-12. 2010
  7. 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
  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
  9. 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
  10. 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

Scientific Experts

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

Detail Information

Publications12

  1. pmc Regulation of glycogen synthase kinase-3 during bipolar mania treatment
    Xiaohong Li
    Beijing Anding Hospital, Capital Medical University, 1720 Seventh Avenue South, Beijing, China
    Bipolar Disord 12:741-52. 2010
    ..Preclinical studies have suggested that glycogen synthase kinase-3 (GSK3) is a potential therapeutic target in bipolar disorder, but evidence of abnormal GSK3 in human bipolar disorder and its response to treatment is still lacking...
  2. pmc Behavioral stress-induced activation of FoxO3a in the cerebral cortex of mice
    Wenjun Zhou
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 35294, USA
    Biol Psychiatry 71:583-92. 2012
    ..The transcription factor FoxO3a is highly expressed in brain, but little is known about the response of FoxO3a to behavioral stress and its impact in the associated behavioral changes...
  3. 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
    ....
  4. pmc Glycogen synthase kinase-3β is a functional modulator of serotonin-1B receptors
    L Chen
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
    Mol Pharmacol 79:974-86. 2011
    ..Future studies may elucidate the significant roles of GSK3 in serotonin neurotransmission and implications of GSK3 inhibitors as functional selective modulators of 5-HT1BR...
  5. pmc Is glycogen synthase kinase-3 a central modulator in mood regulation?
    Xiaohua Li
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    Neuropsychopharmacology 35:2143-54. 2010
    ....
  6. pmc 5-HT1A receptor-regulated signal transduction pathways in brain
    Abigail M Polter
    Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, United States
    Cell Signal 22:1406-12. 2010
    ....
  7. 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
    ....
  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
    ....
  9. 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...
  10. 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...
  11. 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...
  12. 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...