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-3alpha and GSK-3beta. Mice lacking a functional GSK-3alpha gene were engineered in our laboratory; they are viable and display insulin sensitivity. In this study, we have characterized brain functions of GSK-3alpha 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-3beta(+/-) mice, GSK-3alpha mutants display decreased exploratory activity, decreased immobility time and reduced aggressive behavior. However, genetic inactivation of the GSK-3alpha 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-3alpha 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.


CONCLUSIONS
Taken together, these data support a role for the GSK-3alpha gene in CNS functioning and possible involvement in the development of psychiatric disorders.
Kaidanovich-Beilin
Oksana
O
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. beilin@lunenfeld.ca
Lipina
Tatiana V
TV
Takao
Keizo
K
van Eede
Matthijs
M
Hattori
Satoko
S
Laliberté
Christine
C
Khan
Mustafa
M
Okamoto
Kenichi
K
Chambers
John W
JW
Fletcher
Paul J
PJ
MacAulay
Katrina
K
Doble
Bradley W
BW
Henkelman
Mark
M
Miyakawa
Tsuyoshi
T
Roder
John
J
Woodgett
James R
JR
D000374:Aggression / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000002:abnormalities* / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D003863:Depression / Q000473:pathology / Q000503:physiopathology; D004644:Emotions; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D057567:Memory, Long-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D018377:Neurotransmitter Agents / Q000378:metabolism; D012919:Social Behavior
D018377:Neurotransmitter Agents; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha