Abnormalities in brain structure and behavior in GSK-3alpha mutant mice

Background: Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by two genes that generate two related proteins: GSK-3 alpha and GSK-3 beta. Mice lacking a functional GSK-3 alpha gene were engineered in our laboratory; they are viable and display insulin sensitivity. In this study, we have characterized brain functions of GSK-3 alpha KO mice by using a well-established battery of behavioral tests together with neurochemical and neuroanatomical analysis. Results: Similar to the previously described behaviours of GSK-3 beta(+/-)mice, GSK-3 alpha mutants display decreased exploratory activity, decreased immobility time and reduced aggressive behavior. However, genetic inactivation of the GSK-3 alpha gene was associated with: decreased locomotion and impaired motor coordination, increased grooming activity, loss of social motivation and novelty; enhanced sensorimotor gating and impaired associated memory and coordination. GSK-3 alpha KO mice exhibited a deficit in fear conditioning, however memory formation as assessed by a passive avoidance test was normal, suggesting that the animals are sensitized for active avoidance of a highly aversive stimulus in the fear-conditioning paradigm. Changes in cerebellar structure and function were observed in mutant mice along with a significant decrease of the number and size of Purkinje cells. Conclusion: Taken together, these data support a role for the GSK-3 alpha gene in CNS functioning and possible involvement in the development of psychiatric disorders.