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

Abstract

BackgroundGlycogen 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.ResultsSimilar 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.ConclusionTaken together, these data support a role for the GSK-3α gene in CNS functioning and possible involvement in the development of psychiatric disorders.

The intersection of genetic and chemical genomic screens identifies GSK-3α as a target in human acute myeloid leukemia

“…Although 90% homologous in their kinase domains, the α and β isoforms of GSK-3 are not functionally redundant (11,12,32). For example, GSK-3α knockout mice show signs of metabolic and neuronal developmental abnormalities (38,39), while the GSK-3β knockout is lethal late in gestation due to hepatic apoptosis, a phenotype similar to that seen in the NF-κB knockout (40,41). However, both isoforms of GSK-3 need to be inhibited for β-catenin stabilization.…”

Regulation of GSK-3 Activity as A Shared Mechanism in Psychiatric Disorders

“…Reduced GSK-3 activity resulted in behaviors that reflect chronic lithium treatment, whereas overexpression of GSK-3β caused hyperactivity, consistent with mania in humans 38,39 . In addition, overexpression of GSK-3β reverses lithium sensitive behaviors 40 .…”

Regulation of Cell Fate in the Brain by GSK3

“…While GSK3β-knockout mice die in late development due to defects in heart development and/or hepatic apoptosis [22,23], GSK3β-heterozygous mice and GSK3α-knockout (homozygous) mice are viable and display several behavioural defects, including increased anxiety, decreased aggression and memory defects [24][25][26][27][28]. Also, GSK3α-null mice exhibit decreased numbers and size of Purkinje cells in the cerebellum [24]. Conditional overexpression of GSK3β in the forebrain using the doxycycline/Tet system impaired memory and spatial learning in mice [29].…”

“…GSK3 kinase activity is also inhibited by several mood-stabilizers, antidepressants and anti-psychotic drugs [6,79,80], while genetic manipulation of GSK3 activity in mice produces behaviours correlating with mood disorders [24][25][26][27][28]. A single nucleotide polymorphism in the promoter region of GSK3β has also been correlated with onset of Bipolar disorder [81].…”