Possible involvement of the ERK signaling cascade in bipolar disorder: behavioral leads from the study of mutant mice.

Despite the devastating impact that bipolar disorder has on the lives of millions worldwide, little is known for certain about its etiology or pathophysiology. Whereas research has traditionally focused on biogenic amines, it is becoming increasingly more apparent that intracellular pathways are involved in the etiology and treatment of the disease and that a true understanding of the pathophysiology of bipolar disorder must address its neurobiology at different physiological levels, that is, molecular, cellular, systems and behavioral levels. There is now considerable biochemical evidence that the antimanic agents lithium and valproate robustly activate the ERK signaling cascade in therapeutically relevant paradigms. This raises the possibility that this pathway may play a role in the antimanic effects of these agents. The present paper reviews behavioral studies that may shed light on the involvement of the ERK pathway in affective-like behaviors in animals. The available literature suggests that genetic manipulations of the brain-derived neurotrophic factor (BDNF)-ERK kinase pathway produces a variety of changes in affective-like behaviors, with most changes consistent with manic-like behavior. Thus, overall, mice with targeted mutation of the BDNF gene exhibited increased spontaneous locomotion and increased response to acute amphetamine, altered response to chronic cocaine, increased aggression, increase in risk-taking behavior, as demonstrated by time spent in the center of an open field, and changes in eating patterns. Although it has to be acknowledged that the currently available behavioral data from the BDNF-ERK pathway mutants is less than ideal to offer real substantiation relating this pathway to bipolar disorder, the data still supports the possibility that this pathway modulates manic-like behavior in animals, and perhaps mania in humans.