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Genetic inactivation of GSK3α rescues spine deficits in Disc1-L100P mutant mice

Schizophrenia Research, 1, 129, pages 74 - 79

Abstract

Disrupted-in-Schizophrenia 1 (DISC1), a strong candidate gene for schizophrenia and other mental disorders, regulates neurodevelopmental processes including neurogenesis, neuronal migration, neurite outgrowth and spine development. Glycogen synthase kinase-3 (GSK3) directly interacts with DISC1 and also plays a role in neurodevelopment. Recently, our group showed that theDisc1-L100P mutant protein has reduced interaction with both GSK3α and β. Genetic and pharmacological inhibition of GSK3 activity rescued behavioral abnormalities inDisc1-L100P mutant mice. However, the cellular mechanisms mediating these effects of GSK3 inhibition inDisc1mutant mice remain unclear. We sought to investigate the effects of genetic inactivation ofGSK3αon frontal cortical neuron morphology inDisc1L100P mutant mice using Golgi staining. We found a significant decrease in dendritic length and surface area inDisc1-L100P,GSK3αnull and L100P/GSK3αdouble mutants. Dendritic spine density was significantly reduced only inDisc1-L100P and L100P/GSK3α+/− mice when compared to wild-type littermates. There was no difference in dendritic arborization between the various genotypes. No significant rescue in dendritic length and surface area was observed in L100P/GSK3αmutants versus L100P mice, but spine density in L100P/GSK3αmice was comparable to wild-type. Neurite outgrowth and spine development abnormalities induced byDisc1mutation may be partially corrected throughGSK3αinactivation, which also normalizes behavior. However, many of the other dendritic abnormalities in theDisc1-L100P mutant mice were not corrected byGSK3αinactivation, suggesting that only some of the anatomical defects have observable behavioral effects. These findings suggest novel treatment approaches for schizophrenia, and identify a histological read-out for testing other therapeutic interventions.

Keywords: Disrupted-in-schizophrenia 1 (DISC1), Glycogen synthase kinase 3 (GSK3), Mutant mice, Neuronal morphology, Spine density.

Footnotes

a Neuroscience Division, Centre for Addiction and Mental Health, 250 College St, Toronto, Ontario, Canada M5T 1R8

b Department of Pharmacology, University of Toronto, Toronto, Ontario, Canada M5S 1A8

c Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5

d Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A8

e Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada M5T 1R8

f Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada M5S 1A8

lowast Corresponding author at: Neuroscience Division, Centre for Addiction and Mental Health, 250 College Street, Room 711, Toronto, ON, M5T 1R8. Tel.: +1 416 535 8501x4010 (office).