Relevance to Autism

Genetic manipulation of GSK3B in mice has demonstrated its potential role in social behavior: GSK3B knock-in mice exhibited abnormal social preference, showing no significant preference for novel mouse compared to familiar mouse (Mines et al., 2010), while selective deletion of GSK3B in mouse forebrain pyramidal neurons led to anxiolytic and pro-social effects (Latapy et al., 2012). De novo variants in the GSK3B gene, including three de novo loss-of-function variants and a de novo missense variant, were identified in ASD probands from the Autism Sequencing Consortium and the SPARK cohort (De Rubeis et al., 2014; Zhou et al., 2022; Trost et al., 2022). Tan et al., 2024 recently assembled genotype and phenotype data for 15 individuals with GSK3B variants and identified common phenotypes including childhood speech delay (14/15), intellectual disability (11/14), and autism spectrum disorder (8/13); the authors subsequently demonstrated that Gsk3b knockdown in mouse excitatory neurons interfered with dendrite arborization and spine maturation, phenotypes that could not be rescued by expression of mutant GSK3B containing de novo missense variants identified in three affected individuals, all of whom presented with ASD.

Molecular Function

The protein encoded by this gene is a serine-threonine kinase, belonging to the glycogen synthase kinase subfamily. It is involved in energy metabolism, neuronal cell development, and body pattern formation.

External Links

References

Model Summary

Mice with increased activity of GSK3 (21A and 9A knockins) display impaired social memory but have similar anxiety levels and social approach (sociability) as wild type mice.

References