Hyperactivity and enhanced curiosity of mice expressing PKB/SGK-resistant glycogen synthase kinase-3 (GSK-3).
BACKGROUND
Mounting evidence suggests that bipolar disorder symptoms could be favorably influenced by modification of glycogen synthase kinase-3 (GSK-3) activity. Specifically, the well known antimanic and mood stabilizing medications lithium, valproate, olanzapine and clozapine have been shown to inhibit GSK-3 activity. GSK-3 is phosphorylated and thus inhibited by protein kinase B (PKB/Akt) and serum and glucocorticoid inducible kinase (SGK) isoforms. The present study explored, whether PKB/SGK-dependent GSK-3 regulation influences the behavior of mice.


METHODS
Gene-targeted knockin mice with mutated and thus PKB/SGK-resistant GSK-3alpha, beta (gsk-3(KI)) were compared to corresponding wild type mice (gsk-3(WT)). The mice were analyzed by open-field, light-dark (LD-) box, O-maze, emergence test, object exploration test and forced swimming test (FST).


RESULTS
In open-field, LD-box and O-maze, gsk-3(KI) mice displayed a hyperactive and more curious phenotype when compared to wild type mice. Speed and total distance moved as well as rearings were significantly increased in gsk-3(KI) compared to gsk-3(WT) mice. In the O-maze, gsk-3(KI) mice tended to travel a larger distance in the open, unprotected area thangsk-3(WT) mice, and performed significantly more unprotected head dips suggesting decreased anxiety behavior. In the forced swimming test, the immobility time was significantly decreased in gsk-3(KI) mice indicating a phenotype less prone to depression. Moreover, gsk-3(KI)mice were less sensitive to the application of chronic mild stress and showed a decreased HPA axis activity.


CONCLUSIONS
The present observations disclose a significant role of PKB/SGK-dependent regulation of GSK-3 in the control of activity, anxiety and proneness to depression. Accordingly, mice expressing SGK/PKB resistant GSK-3 may be a valuable model of hyperactivity and mania.
Department of Physiology I, University of Tuebingen, 72076 Tuebingen, Germany.
Teresa F
TF
Ackermann
Daniela S
DS
Kempe
Florian
F
Lang
Undine E
UE
Lang
D000818:Animals; D003863:Depression / Q000235:genetics / Q000378:metabolism; D005106:Exploratory Behavior; D005260:Female; D005786:Gene Expression Regulation; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006948:Hyperkinesis / Q000235:genetics / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
D038362:Glycogen Synthase Kinase 3; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000099184:Serum-Glucocorticoid Regulated Kinases