Identifying Proteins and Genes in the Brain to Battle Bipolar Disorder
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
Annual Research Symposium Exhibits the Strength of UAB Psychiatry
The UAB Department of Psychiatry held its Fourth Annual Research Symposium on April 13, 2010. The event included poster presentations from our faculty, graduate students, and residents followed by three oral presentations. Two Department of Psychiatry faculty members presented: Dr. Jacinda Hammel, Implementing Evidence Based Practices and Dr. Karen Gamble, Night Owls and Early Birds: Circadian Regulation and Mental Health. A special presentation, Medial Prefrontal Cortex in PTSD: The Role on Contextual Processing, was given by our distinguished guest, Dr. Israel Liberzon. Dr. Liberzon is the Theophile Raphael Professor of Neuroscience and Professor of Psychiatry and Psychology at the University of Michigan.
UAB Research Highlighted at NARSAD Symposium
The UAB Department of Psychiatry and the Comprehensive Neuroscience Center hosted NARSAD’s Healthy Minds Across America symposium Saturday, April 10th. The National Alliance for Research on Schizophrenia and Depression (NARSAD) supports research into prevention and treatment of mental illnesses. The event was designed to educate the public about the research being done at the national and local levels on the topics of schizophrenia, depression, bipolar disorder, anxiety, autism, PTSD, and addiction. UAB was one of over 45 institutions across the nation that hosted a symposium. Presentations were given by: Adrienne Lahti, M.D.; Dr. F. Cleveland Kinney, M.D.; and Karen Gamble, Ph.D. Dr. Lahti’s presentation was titled: “Does brain imaging help us understand the mechanism of action of antipsychotic drugs?”; Dr. Kinney’s talk was titled: “Alzheimer’s Disease: An update on management and treatment”; and Dr. Gamble’s presentation was titled: “Night owls and early birds: Circadian regulation and mood disorders.” Below are pictures taken at the event. If you would like to learn more about NARSAD and the work they do please visit their web site: www.narsad.org
Disruption of Sleep May Contribute to Many Symptoms of Mental Illness
Karen Gamble joined the Department of Psychiatry and Behavioral Neurobiology at UAB in September 2009, after completing her postdoctoral training at Vanderbilt University. Dr. Gamble holds a Ph.D. in Behavioral Neuroscience and received a prestigious Pathway to Independence Award from the National Institutes of Health, for a project entitled “Integration of Photic and Nonphotic Signaling in the Circadian Pacemaker.”
The focus of Dr. Gamble’s research is the investigation of sleep timing controlled by the brain’s clock (circadian system). Clock disturbances can greatly disrupt sleep and are characteristic of many mental health disorders including depression and schizophrenia. Studies have shown that disruption in the timing of sleep can worsen the symptoms of many psychiatric disorders. Furthermore, the symptoms resulting from disrupted sleep timing, for example, in shift workers or during ‘jetlag’, can be mistaken for psychiatric illness in people who do not have a psychiatric disorder. On a much broader scale, shift work has been associated with an increased risk of developing cardiovascular disease, metabolic and gastrointestinal disorders, depression, as well as cancer. In fact, in an animal model of chronic jet lag, circadian researcher Alec Davidson, Ph.D. and colleagues at Morehouse Medical School have shown that geriatric animals had greatly increased mortality rates compared to un-shifted controls. Dr. Gamble’s research aims to determine how genetic and environmental disruption of the circadian system can lead to mental illness and other medical problems, using animal models of clock-controlled sleep disturbances.
The brain’s master clock is located in a region called the suprachiasmatic nucleus (SCN) of the hypothalamus. The clock synchronizes with the environment, for example with daylight, due to the activity of “clock” genes called Period1 and Period2. Clock gene activity can be measured in real-time using glowing reporter proteins from fireflies and jelly fish that are artificially linked to the clock genes. These reporters can be used to record electrical signals (the primary language of brain cells) and gene activity at the same time in individual living brain cells. Twenty-four hour gene activity continues for many months after culturing brain slices containing the SCN, and this property allows for examination of the chemical signals that are critical for clock function. Recently, Dr. Gamble and her colleagues demonstrated the importance of a well-known chemical signal in the SCN, gastrin releasing peptide, in the process of resetting the clock and activating clock genes. In addition to light, other stimuli can also reset the clock, such as arousal and exercise. In the future, she plans to use similar strategies to investigate how the clock’s cells interpret and respond to conflicting stimuli such as when exercise and light occur together.
In an effort to extend the basic knowledge of circadian rhythms to humans, Dr. Gamble has explored genetic and environmental predictors of adaptation to night-shift work in hospital nurses. All of us who have benefited from nurse care in hospitals will be interested in how nurses adapt, or do not adapt, to shift work behaviorally and genetically. In her research, Dr. Gamble and colleagues at Vanderbilt University identified five novel sleep strategies that nightshift nurses used for their days-off. Nurses who used sleep deprivation in order to switch between day- and night-shifts were the most poorly adapted to night-shift. In addition, this study showed that some genotypes of circadian clock genes are associated with alcohol and caffeine consumption, sleepiness, sleep duration, and tendency to be a night owl. Finally, this research demonstrated genes can interact with the environment because some circadian genotypes only contributed to behavior under certain shift conditions.
At UAB, Dr. Gamble is collaborating with Dr. Rachel Fargason, Dr. Xiaohua Li, and Roberta May in a clinical trial exploring new treatments for people with attention deficit hyperactivity disorder (ADHD) with insomnia. This collaborative group plans to test the idea that some ADHD patients experience insomnia because they have late clocks and are thus, night owls. Insomnia worsens the symptoms of ADHD. They expect treatment with a drug that enhances the effects of melatonin will reset the clock in these patients and improve their symptoms.
We are delighted to welcome Dr. Gamble to the Department and look forward to seeing interesting research developments from her laboratory on this important clinical problem.
TASC and Foster Cook: The Man Behind the Program
Mr. Foster Cook, on the faculty of the Department of Psychiatry since 1978 and the director of the Substance Abuse Programs, has provided the necessary leadership and vision to build a dynamic model of research, direct services, and social justice advocacy through the UAB Treatment Alternatives for Safer Communities (TASC). His grandparents were missionaries to Korea in the early 1900’s and his family history of public service has imprinted well.
Mr. Cook’s attributes include a remarkable understanding of: salient political forces, the power of judges and law enforcement, the burden of not treating those with addiction caught up in the judicial system, and cost-effective evidence based treatment combined with a passionate commitment to advocacy for a disenfranchised population. Starting in the mid to late 80’s, his aggressive solicitation of federal dollars brought resources into the local systems that have helped drive policy-topractice reforms. Over the years, Mr. Cook has been awarded over 16 million dollars to fund such entities as: drug prevalence research, implementation of drug courts, and mental health courts, and expanded access to substance abuse treatment. His vision, diligence, and leadership have created, preserved and sustained a system of care that saves money, but more importantly, saves lives. He and TASC have never stopped working to help those who so desperately need assistance in the State of Alabama.
The UAB Treatment Alternatives for Safer Communities (TASC) originated through a federal grant proposal in The White House Special Action Office for Drug Abuse Prevention. TASC was established as a case management program for felony offenders with serious substance abuse and addiction disorders. In 1973, the Law Enforcement Assistance Administration (LEAA) and the National Institute in Drug Abuse funded 13 TASC sites, which included the UABTASC Program. TASC was the first effort to bring together, through a formal partnership, the criminal justice system and the substance abuse treatment system. It remains the oldest operational TASC Program in the country.
Mr. Foster Cook, the current director, helped implement the program, then housed in the Birmingham City jail, in 1973. Mr. Bill Cox, a local parole official, was director until 1977. At that time, federal funding had dissipated and local city and county funding was obtained for continuation of the program. UAB Department of Psychiatry, then headed by Dr. Patrick Linton, provided the administrative infrastructure and support. The partnership between UAB Psychiatry and TASC expanded in mission and scope under Mr. Cook’s leadership. The UAB Methadone Clinic merged with TASC and the outpatient UAB Drug Abuse Program at Smolian Clinic in 1980.
In the early 90’s, the Jefferson County jail became dangerously overcrowded. To alleviate these conditions, the county utilized UAB-TASC as a jail diversion/pre-trial program. UAB-TASC also implemented one of the states earliest drug court programs; now the largest drug court in Alabama. Presently, Jefferson County incorporates two Judicial Circuits-Birmingham and Bessemer. Parallel programs, including pre-trial release and a drug court, were created in Bessemer to match services with the Birmingham Judicial Circuit.
In 1992, The National Institute of Drug Abuse selected 5 TASC programs for evaluation by the RAND Corporation and the UCLA Department of Neuropsychiatry. UAB-TASC was one of the sites and the research team compared TASC program outcomes with criminal justice clients who did not receive TASC services. UAB-TASC clients received significantly more services in every domain than the control group (jobs, drug treatment, HIV screening, mental health, urine screening) and responded with lowered re-arrest rates for high-risk felony offenders.
In 1996, UAB-TASC was one of three sites in the nation to be selected as a demonstration model for the Break-The-Cycle Project. The White House office of National Drug Control Policy funded this unique effort to expand TASC core operational elements (early intervention, assessment, referral to appropriate community services and assertive case management) into a system wide continuum from arrest through final sentencing and adjudication. The Urban Institute provided the outcome evaluation, which concluded that TASC supervision lowered recidivism dramatically (30%) compared to a control group.
Upon completion of this project, the local justice system retained the improvements that were implemented under Break-The-Cycle. In 2001, TASC targeted those with severe mental illness who were incarcerated for longer periods of time and could not access the critical services necessary for management of their mental illness. UAB-TASC collaborated with the National Alliance for the Mentally Ill (NAMI), county government and the courts to complement two mental health courts in Birmingham and Bessemer. These courts are administered similar to the drug court model of intermediated sanction and incentives. UAB-TASC has also served the juvenile offender population since the mid 1980’s. The Adolescent Substance Abuse Program (ASAP) is contracted with the juvenile court system and provides urine screening and substance abuse treatment, prevention and monitoring for the court.
As can be readily observed, since 1973 UAB-TASC has evolved considerably, managing to combine the collective efforts of treatment providers, law enforcement, and the judiciary, to offer populations challenged by substance and drug dependence a breadth of services that have proven, overtime, to be profoundly effective. Supported by federal funding, Mr. Cook implemented the core program elements and networks the have proven effective for over 35 years.