Mechanisms Involved in Mood Disorders and Treatments
Richard S. Jope, Ph.D.
Research in this laboratory is focused on identifying underlying causes, and developing new treatments for, disorders of the central nervous system (CNS), including mood disorders, multiple sclerosis, and Fragile X Syndrome, and is presently funded by two R01 grants from the NIH and one grant from the FRAXA Foundation.
Understanding the etiologies of mood disorders, which have a lifetime prevalence of ~20% of the population of the United States, is important for the development of more effective therapeutic interventions for these prevalent diseases. This research has recently focused on the therapeutic actions of inhibitors of glycogen synthase kinase-3 (GSK3) in transgenic mouse models of depression and bipolar disorder (manic-depression). This led to our findings that inhibiting GSK3 enhanced neuronal resilience to multiple types of neuronal stressors, and identification of regulatory effects of GSK3 on mood-relevant behaviors and neurogenesis in mice. This research has been supported by an R01 grant from the NIH that is currently in its 27th year of funding.
Our research has also revealed profound regulatory effects of GSK3 in immune system functions. The understanding of neural-immune system interactions is currently undergoing a revolution. Previous descriptions of the CNS as “immune-privileged” were often over-interpreted to such an extent that immune actions in the CNS were thought to be largely limited to autoimmune diseases with disruption of the blood-brain barrier. In contrast, it is now evident that the CNS remains under constant immune surveillance and that both innate and adaptive immune system mediators tremendously affect both the healthy and diseased CNS. Recognition that the onset, magnitude, and duration of psychiatric and neurological diseases, as well as responses to traditional therapeutic interventions, are impacted by immune mediators emphasizes the importance of clarifying neural-immune system interactions and identifying potential therapeutic targets. We discovered that GSK3 promotes inflammatory responses of the innate immune system and that inhibition of GSK3 prevented, and reversed, the development of experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. This led to our current studies addressing novel mechanisms involved in neural-immune system interactions, potential regulatory actions of GSK3, and their links to depression and multiple sclerosis in mouse models. This research is currently funded by an R01 grant from the NIH.
Fragile X Syndrome is the most common genetic cause of mental retardation and also results in autistic characteristics, but no therapeutic interventions are effective in Fragile X Syndrome patients. We found that GSK3 is not adequately controlled in the mouse model of Fragile X Syndrome and that administration of lithium and other inhibitors of GSK3 significantly ameliorate biochemical, behavioral and cognitive abnormalities. This research is in its third year of funding by the FRAXA Foundation.
Altogether, our research has led these fields into new areas, has been highly productive, and has contributed to the training of many graduate students and postdoctoral fellows.