GSK3 Influences Social Preference and Anxiety-Related Behaviors during Social Interaction in a Mouse Model of Fragile X Syndrome and Autism

Abstract

BackgroundNearly 1% of children in the United States exhibit autism spectrum disorders, but causes and treatments remain to be identified. Mice with deletion of the fragile X mental retardation 1 (Fmr1) gene are used to model autism because loss of Fmr1 gene function causes Fragile X Syndrome (FXS) and many people with FXS exhibit autistic-like behaviors. Glycogen synthase kinase-3 (GSK3) is hyperactive in brains of Fmr1 knockout mice, and inhibition of GSK3 by lithium administration ameliorates some behavioral impairment in these mice. We extended our studies of this association by testing whether GSK3 contributes to socialization behaviors. This used two mouse models with disrupted regulation of GSK3, Fmr1 knockout mice and GSK3 knockin mice, in which inhibitory serines of the two isoforms of GSK3, GSK3α and GSK3β, are mutated to alanines, leaving GSK3 fully active.Methodology/Principal FindingsTo assess sociability, test mice were introduced to a restrained stimulus mouse (S1) for 10 min, followed by introduction of a second restrained stimulus mouse (S2) for 10 min, which assesses social preference. Fmr1 knockout and GSK3 knockin mice displayed no deficit in sociability with the S1 mouse, but unlike wild-type mice neither demonstrated social preference for the novel S2 mouse. Fmr1 knockout mice displayed more anxiety-related behaviors during social interaction (grooming, rearing, and digging) than wild-type mice, which was ameliorated by inhibition of GSK3 with chronic lithium treatment.Conclusions/SignificanceThese results indicate that impaired inhibitory regulation of GSK3 in Fmr1 knockout mice may contribute to some socialization deficits and that lithium treatment can ameliorate certain socialization impairments. As discussed in the present work, these results suggest a role for GSK3 in social behaviors and implicate inhibition of GSK3 as a potential therapeutic.

Epilepsy and Autism

“…FMRP knockout mice show ALB (Mines et al 2010;Paz et al 2013;Tyzio et al 2014). The knockouts have a significant increase in global protein synthesis and in protein synthesis at the synapse (Bassell and Warren 2008).…”

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

“…• lithium [113,122,123,134,[153][154][155] specific GSK3β antagonists [122,134] PAK Genetic (dn) Cellular: dendritic spine density (partially) [156] N/A N/A Shown are genetic and pharmacological rescue strategies and their effects in Fmr1 knockout mice. The following strategies were confirmed in studies using Drosophila models of fragile X syndrome (FXS): metabotropic glutamate receptor (mGluR) [167], gamma-aminobutyric acid (GABA) [168] (but see [169]), lithium [167], minocycline [170], phosphodiesterase-4 (PDE-4) [ A recent study suggested that simultaneous stimulation of D1R and serotonin (5HT) receptors rescued impaired synaptic AMPA receptor insertion and plasticity, and improved fear conditioning and Y maze learning deficits [115].…”

Molecular Mechanisms Regulating Impaired Neurogenesis of Fragile X Syndrome Human Embryonic Stem Cells

“…A major finding in brain samples of Fmr1 -/-mice is the abnormally high levels of GSK3b, a key kinase shown to play critical roles in several molecular pathways, including MAPK, Cyclin, Akt, and the canonical Wnt/b-catenin signaling pathway [26,[45][46][47]. The role of GSK3b, as part of the canonical Wnt/bcatenin signaling pathway, was shown to be important during adult neurogenesis in the murine hippocampus [29] and in FXS pathology in Fmr1 -/-mice [27,28].…”