Accumulating evidence shows inflammation strongly influences the development and treatment of depression, a debilitating disease with a lifetime incidence of ~20%. Markers of Inflammation often are increased in the serum of depressed patients, interferon administration can induce depression, """"""""psychological"""""""" stresses that can induce depression increase inflammatory cytokines in humans and rodents, administration of inflammatory cytokines induces depression-like behaviors in rodents, in humans increased cytokines associated with a mild stimulation of the primary host defense system has negative effects on emotions, antidepressants have anti-inflammatory effects, and immune activation in patients with major depression is associated with resistance to antidepressant treatment. Therefore, in order to understand and design improved therapeutics for depression, it is important to identify mechanisms regulating neuroinflammation, inflammatory molecule accumulation in the CNS. Glycogen synthase kinase-3 (GSK3) recently was found to be a powerful regulator of cytokine production in the periphery. We extended this to the CNS, e.g., showing that GSK3 inhibitors reduce by >90% the production of the proinflammatory cytokine interleukin-6 in astrocytes and microglia. We also found that GSK3 inhibitors promote tolerance to inflammation, down-regulating inflammatory responses to repeated inflammatory stimuli, which may be particularly important in controlling chronic inflammation that is likely associated with mood disorders. GSK3 also has profound influences in mood disorders, it is inhibited by mood stabilizers and antidepressants, pharmacological or genetic reduction of GSK3 activity reduces depression-like behaviors in rodents, and evidence in postmortem brain samples and serum from humans indicate GSK3 is abnormally active in mood disorders. We recently found GSK3 is activated in mouse brain by the learned helplessness model of depression. Taken together, these findings suggest that the pro-inflammatory action of GSK3 may contribute to its promotion of mood disorders, and that the therapeutic actions of mood stabilizers and antidepressants that inhibit GSK3 may involve anti-inflammatory effects. Thus, studies of the inflammation system provide a model system to study how GSK3 regulates key processes that are likely involved in mood disorders: epigenetics, tolerance, and behavior.
These aims provide independent but associated goals that will identify new mechanisms by which dysregulated GSK3 can contribute to mood disorders and identify how therapeutic interventions ameliorate these outcomes.
Specific Aim 1 will test the hypothesis that GSK3 regulates innate and adaptive immune system in the brain during depressive-like behavior.
Specific Aim 2 will test the hypothesis that GSK3 regulates epigenetics, using changes induced by inflammatory stimuli as a model.
Specific Aim 3 will test the hypothesis that GSK3 promotes depression-like behavioral responses to inflammatory and environmental stress.

Public Health Relevance

Mood disorders afflict approximately 20% of the population of the United States at some point in their lifetimes. However, because the underlying biochemical causes of these diseases are not known, treatments often do not adequately provide therapeutic benefits. These diseases appear to develop due to genetic susceptibilities, life experiences, and environmental conditions, particularly stress. This project will address potential causes of susceptibilities to mood disorders and examine actions of mood stabilizers and antidepressants that may contribute to their therapeutic effects. The goals are to clarify potential causative mechanisms and discern how these are altered by therapeutic interventions with the aim of developing better therapeutic interventions for mood disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Transition Award (R00)
Project #
Application #
Study Section
Special Emphasis Panel (NSS)
Program Officer
Desmond, Nancy L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
Zip Code
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
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
Beurel, Eleonore; Grieco, Steven F; Jope, Richard S (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther 148:114-31
Beurel, Eléonore; Harrington, Laurie E; Buchser, William et al. (2014) Astrocytes modulate the polarization of CD4+ T cells to Th1 cells. PLoS One 9:e86257
Beurel, Eléonore; Nemeroff, Charles B (2014) Interaction of stress, corticotropin-releasing factor, arginine vasopressin and behaviour. Curr Top Behav Neurosci 18:67-80

Showing the most recent 10 out of 20 publications