The long-term goal of this project is to identify cellular mechanisms of action of lithium and other mood stabilizers in order to contribute to understanding the underlying pathophysiology and to enhance treatment of mood disorders. To achieve this, four specific aims are to be addressed. 1. Lithium is a direct inhibitor of glycogen synthase kinase-3 (GSK3), and recently we showed this action is amplified in vivo in mouse brain by phosphorylation of select pools of GSK3, substantially increasing the inhibitory effect of a therapeutic level of lithium.
Specific Aim 1 will examine this amplification mechanism inhibiting the activity of GSK3, the influence of lithium, and this mechanism will be examined in Aims 2-4. 2. We recently discovered that serotonergic activity inhibits GSK3 in mouse brain in vivo, revealing a direct link between serotonergic activity and lithium's target.
Specific Aim 2 will examine the in vivo mechanisms by which serotonergic activity regulates GSK3, the serotonin receptor subtypes that are involved, the effects of mood stabilizers and antidepressants, and signaling pathways involved. 3. The goal of the third aim is to establish an in vivo model of pathological activation of GSK3 that is counteracted by mood stabilizers and antidepressants. We will follow-up our recent findings that In mouse brain in vivo hypoxia rapidly and robustly activates GSK3 and this is blocked by in vivo administration of mood stabilizers or imipramine.
Specific Aim 3 will test the hypothesis that hypoxia activates GSK3 and mood stabilizers and antidepressants attenuate this GSK3 activation and will investigate mechanisms underlying these interactions in cultured cells, since this provides the only model of pathophysiological GSK3 activation in vivo that is attenuated by these therapeutic agents. 4. Substantial evidence indicates that neurogenesis may be impaired in mood disorders and be promoted by therapeutic agents.
Specific Aim 4 will test the hypothesis that GSK3, which often promotes apoptosis, is activated during apoptosis of neural precursor cells and that inhibition of GSK3 promotes survival.
This aim will also test if inhibition of GSK3 promotes precursor cell differentiation or survival of differentiated cells. Overall, this project will continue to provide leading-edge insight into mechanisms that may underlie the pathology of mood disorders and the actions of mood stabilizers. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH038752-23
Application #
7218686
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Nadler, Laurie S
Project Start
1984-02-01
Project End
2011-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
23
Fiscal Year
2007
Total Cost
$300,222
Indirect Cost
Name
University of Alabama Birmingham
Department
Psychiatry
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Grieco, Steven F; Cheng, Yuyan; Eldar-Finkelman, Hagit et al. (2017) Up-regulation of insulin-like growth factor 2 by ketamine requires glycogen synthase kinase-3 inhibition. Prog Neuropsychopharmacol Biol Psychiatry 72:49-54
Jope, Richard S; Cheng, Yuyan; Lowell, Jeffrey A et al. (2017) Stressed and Inflamed, Can GSK3 Be Blamed? Trends Biochem Sci 42:180-192
Grieco, Steven F; Velmeshev, Dmitry; Magistri, Marco et al. (2017) Ketamine up-regulates a cluster of intronic miRNAs within the serotonin receptor 2C gene by inhibiting glycogen synthase kinase-3. World J Biol Psychiatry 18:445-456
Pardo, Marta; Beurel, Eleonore; Jope, Richard S (2017) Cotinine administration improves impaired cognition in the mouse model of Fragile X syndrome. Eur J Neurosci 45:490-498
Pardo, M; Abrial, E; Jope, R S et al. (2016) GSK3? isoform-selective regulation of depression, memory and hippocampal cell proliferation. Genes Brain Behav 15:348-55
Beurel, Eléonore; Grieco, Steven F; Amadei, Celeste et al. (2016) Ketamine-induced inhibition of glycogen synthase kinase-3 contributes to the augmentation of ?-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor signaling. Bipolar Disord 18:473-480
Cheng, Yuyan; Pardo, Marta; Armini, Rubia de Souza et al. (2016) Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior. Brain Behav Immun 53:207-222
Cheng, Yuyan; Jope, Richard S; Beurel, Eleonore (2015) A pre-conditioning stress accelerates increases in mouse plasma inflammatory cytokines induced by stress. BMC Neurosci 16:31
Pardo, Marta; King, Margaret K; Perez-Costas, Emma et al. (2015) Impairments in cognition and neural precursor cell proliferation in mice expressing constitutively active glycogen synthase kinase-3. Front Behav Neurosci 9:55
Beurel, Eleonore; Grieco, Steven F; Jope, Richard S (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther 148:114-31

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