Bipolar disorder is a severe type of mood disorder with uncontrollable mood swings between mania and depression. The illness afflicts approximately 2% of the population and is debilitating and life-threatening if untreated. However, the mechanisms affecting brains of bipolar disorder patients are unknown, which largely limits the treatment options for these patients. Therefore, mechanistic insights gained by identifying proteins and genes in brain that contribute to both manic and depressive symptoms are critical for deciphering the pathophysiology of bipolar disorder and developing new therapeutic interventions.
A protein called glycogen synthase kinase-3 (GSK3) has been suspected to be a risk factor contributing to bipolar disorder since the therapeutically effective mood stabilizer lithium can stop its function in the brain. As a joint effort, research teams led by Drs. Xiaohua Li and Richard Jope in the UAB Department of Psychiatry and Behavioral Neurobiology have conducted research in understanding the role of GSK3 in the therapeutics of bipolar disorder. They have found that the inhibitory serine phosphorylation of GSK3 is a major regulatory mechanism controlling GSK3 by several bipolar disorder treatments, including lithium, other mood stabilizers, some antipsychotics, and antidepressants.
In their most recent study published in Neuropsychopharmacology, a high impact journal in psychiatric research, they tested a hypothesis that insufficient serine phosphorylation of GSK3 poses a risk for developing symptoms characteristic of bipolar disorder. Indeed, serine-phosphorylation of GSK3 in animal brains was reduced when hyperactivity was induced by amphetamine and when depressive behaviors were induced by stress. When tested in an animal model in which GSK3 is genetically engineered to block the inhibitory serine-phosphorylation, they found that insufficient GSK3 serine phosphorylation increased susceptibility of animals to amphetamine-induced hyperactivity and to stress-induced depressive-like behaviors. Importantly, reduced serine-phosphorylation of GSK3 was found in blood cells from bipolar disorder patients who were either in a manic or a depressive episode, and the amplitude of GSK3 reduction correlates with severity of clinical symptoms. Therefore, proper control of GSK3 by serine-phosphorylation is an important mechanism that regulates mood stabilization, and new drugs developed specifically against GSK3 serine phosphorylation may have important therapeutic implication in bipolar disorder. Additionally, animals with genetically blocked GSK3 serine-phosphorylation may provide a valuable model to study bipolar disorder.
Neuropsychopharmacology, in press (2010)
Deficiency in the inhibitory serine-phosphorylation of glycogen synthase kinase-3 increases sensitivity to mood disturbances
Abigail Polter1,2, Eleonore Beurel1, Sufen Yang1, Rakesha Garner1, Ling Song1, Courtney A. Miller2, J. David Sweatt2, Lori McMahon2,3, Alfred A. Bartolucci4, Xiaohua Li1,2*§, and Richard S. Jope1*§ *These authors contributed equally to this project
1Department of Psychiatry and Behavioral Neurobiology, 2Department of Neurobiology, 3Department of Physiology and Biophysics, 4Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA