title: Neurological characterization of mice deficient in GSK3α highlight pleiotropic physiological functions in cognition and pathological activity as Tau kinase.
abstract: BACKGROUND
  GSK3β is involved in a wide range of physiological functions, and is presumed to act in the pathogenesis of neurological diseases, from bipolar disorder to Alzheimer's disease (AD). In contrast, the GSK3α isozyme remained largely ignored with respect to both aspects.
  
  
  RESULTS
  We generated and characterized two mouse strains with neuron-specific or with total GSK3α deficiency. Behavioral and electrophysiological analysis demonstrated the physiological importance of neuronal GSK3α, with GSK3β not compensating for impaired cognition and reduced LTP. Interestingly, the passive inhibitory avoidance task proved to modulate the phosphorylation status of both GSK3 isozymes in wild-type mice, further implying both to function in cognition. Moreover, GSK3α contributed to the neuronal architecture of the hippocampal CA1 sub-region that is most vulnerable in AD. Consequently, practically all parameters and characteristics indicated that both GSK3 isoforms were regulated independently, but that they acted on the same physiological functions in learning and memory, in mobility and in behavior.
  
  
  CONCLUSIONS
  GSK3α proved to be regulated independently from GSK3β, and to exert non-redundant physiological neurological functions in general behavior and in cognition. Moreover, GSK3α contributes to the pathological phosphorylation of protein Tau.
authors.affiliation: Department Human Genetics, Experimental Genetics Group - LEGTEGG, KULeuven, Leuven, Belgium.
authors.forename: Hervé
authors.initials: H
authors.lastname: Maurin
authors.forename: Benoit
authors.initials: B
authors.lastname: Lechat
authors.forename: Ilse
authors.initials: I
authors.lastname: Dewachter
authors.forename: Laurence
authors.initials: L
authors.lastname: Ris
authors.forename: Justin V
authors.initials: JV
authors.lastname: Louis
authors.forename: Peter
authors.initials: P
authors.lastname: Borghgraef
authors.forename: Herman
authors.initials: H
authors.lastname: Devijver
authors.forename: Tomasz
authors.initials: T
authors.lastname: Jaworski
authors.forename: Fred
authors.initials: F
authors.lastname: Van Leuven
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight; D001921:Brain / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000201:enzymology / Q000473:pathology; D003071:Cognition / Q000502:physiology*; D003433:Crosses, Genetic; D005260:Female; D058685:Genetic Pleiotropy; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007248:Infertility, Male / Q000201:enzymology / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D009929:Organ Size; D009928:Organ Specificity; D010641:Phenotype; D010766:Phosphorylation; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D007527:Isoenzymes; D050505:Mutant Proteins; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha; C045073:Cre recombinase; D019426:Integrases