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

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Molecular Brain (Impact Factor: 4.9). 11/2009; 2(1):35. DOI: 10.1186/1756-6606-2-35
Source: PubMed


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

Download full-text


Available from: James R Woodgett
  • Source
    • "Previously, mice overexpressing GSK3β were reported to exhibit impaired spatial learning in the Morris water maze (Hernandez et al., 2002), further indicating that excessive GSK3β impairs spatial learning and memory. Oppositely, mice deficient in GSK3α did not exhibit impaired performance in a variety of tasks with a spatial component (Kaidanovich-Beilin et al., 2009; Hurtado et al., 2012; Maurin et al., 2013). In summary, all three cognitive tasks that were examined revealed sensitivities to abnormal activation of GSK3, and novel object recognition was specifically sensitive to GSK3β activation, temporal ordering was the least sensitive as it was only impaired by activation of both GSK3 isoforms, and coordinate spatial processing was the most sensitive to impairment by active GSK3 as it was impaired by activation of either GSK3 isoform. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Abnormally active glycogen synthase kinase-3 (GSK3) contributes to pathological processes in multiple psychiatric and neurological disorders. Modeled in mice, this includes increasing susceptibility to dysregulation of mood-relevant behaviors, impairing performance in several cognitive tasks, and impairing adult hippocampal neural precursor cell (NPC) proliferation. These deficits are all evident in GSK3α/β knockin mice, in which serine-to-alanine mutations block the inhibitory serine phosphorylation regulation of both GSK3 isoforms, leaving GSK3 hyperactive. It was unknown if both GSK3 isoforms perform redundant actions in these processes, or if hyperactivity of one GSK3 isoform has a predominant effect. To test this, we examined GSK3α or GSK3β knockin mice in which only one isoform was mutated to a hyperactive form. Only GSK3β, not GSK3α, knockin mice displayed heightened vulnerability to the learned helplessness model of depression-like behavior. Three cognitive measures impaired in GSK3α/β knockin mice demonstrated differential regulation by GSK3 isoforms. Novel object recognition was impaired in GSK3β, not GSK3α, knockin mice, whereas temporal order memory was not impaired in GSK3α or GSK3β knockin mice, and coordinate spatial processing was impaired in both GSK3α and GSK3β knockin mice. Adult hippocampal NPC proliferation was severely impaired in GSK3β knockin mice, but not impaired in GSK3α knockin mice. Increased activity of GSK3β, in the absence of over-expression or disease pathology, is sufficient to impair mood regulation, novel object recognition, and hippocampal NPC proliferation, whereas hyperactive GSK3α individually does not impair these processes. These results demonstrate that hyperactivity of the two GSK3 isoforms execute non-redundant effects on these processes.
    Full-text · Article · Jan 2016 · Genes Brain and Behavior
  • Source
    • "For example, muscarinic acetylcholine receptor M2 KO mice in one study demonstrated no impairments in fear conditioning, despite the fact that M2 KO led to impairment in the acquisition of a passive avoidance task [30]. In another example, GSK-3α KO mice exhibited a deficit in fear conditioning, but their learning and memory performance in the passive avoidance test was normal [31]. Additional studies, including histological and electrophysiological analyses, will be required to elucidate whether and how CD47 contributes to the regulation of learning and memory in mice. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cluster of differentiation 47 (CD47) is a member of the immunoglobulin superfamily which functions as a ligand for the extracellular region of signal regulatory protein α (SIRPα), a protein which is abundantly expressed in the brain. Previous studies, including ours, have demonstrated that both CD47 and SIRPα fulfill various functions in the central nervous system (CNS), such as the modulation of synaptic transmission and neuronal cell survival. We previously reported that CD47 is involved in the regulation of depression-like behavior of mice in the forced swim test through its modulation of tyrosine phosphorylation of SIRPα. However, other potential behavioral functions of CD47 remain largely unknown. In this study, in an effort to further investigate functional roles of CD47 in the CNS, CD47 knockout (KO) mice and their wild-type littermates were subjected to a battery of behavioral tests. CD47 KO mice displayed decreased prepulse inhibition, while the startle response did not differ between genotypes. The mutants exhibited slightly but significantly decreased sociability and social novelty preference in Crawley's three-chamber social approach test, whereas in social interaction tests in which experimental and stimulus mice have direct contact with each other in a freely moving setting in a novel environment or home cage, there were no significant differences between the genotypes. While previous studies suggested that CD47 regulates fear memory in the inhibitory avoidance test in rodents, our CD47 KO mice exhibited normal fear and spatial memory in the fear conditioning and the Barnes maze tests, respectively. These findings suggest that CD47 is potentially involved in the regulation of sensorimotor gating and social behavior in mice.
    Full-text · Article · Feb 2014 · PLoS ONE
  • Source
    • "The structural similar kinase domains predict that GSK3 isozymes share physiological functions. Nevertheless, GSK3β deficient mice die in utero [20] in contrast with viability of GSK3α deficient mice [21]. This extreme difference in outcome demonstrates their non-redundant physiological functions, which still need to be detailed in vivo. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · May 2013 · Molecular Brain
Show more