Research

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

Oksana Kaidanovich-Beilin¹ , Tatiana V Lipina¹ , Keizo Takao^2,3,4,5 , Matthijs van Eede⁶ , Satoko Hattori^2,4,5 , Christine Laliberté⁶ , Mustafa Khan¹ , Kenichi Okamoto^1,9 , John W Chambers⁷ , Paul J Fletcher^7,9 , Katrina MacAulay¹ , Bradley W Doble⁸ , Mark Henkelman^6,9 , Tsuyoshi Miyakawa^2,3,4,5 , John Roder^1,9 and James R Woodgett^1,9

¹  Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada

²  Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake 470-1192, Japan

³  Genetic Engineering and Functional Genomics Group, Frontier Technology Center, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

⁴  Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Kawaguchi, Japan

⁵  Section of Behavior Analysis, Center for Genetic Analysis of Behavior, National Institute for Physiological Sciences, Okazaki, Japan

⁶  Mouse Imaging Center, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada

⁷  Center for Addiction and Mental Health, Toronto, Canada

⁸  McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON L8N 3Z5, Canada

⁹  University of Toronto, Departments of Medical Biophysics, Psychology, Psychiatry and Molecular & Medical Genetics, Toronto, ON M5S 1A1, Canada

author email corresponding author email

Molecular Brain 2009, 2:35doi:10.1186/1756-6606-2-35

Published:	19 November 2009

Abstract

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-3α and GSK-3β. Mice lacking a functional GSK-3α gene were engineered in our laboratory; they are viable and display insulin sensitivity. In this study, we have characterized brain functions of GSK-3α 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-3β^+/-mice, GSK-3α mutants display decreased exploratory activity, decreased immobility time and reduced aggressive behavior. However, genetic inactivation of the GSK-3α 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-3α 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-3α gene in CNS functioning and possible involvement in the development of psychiatric disorders.