Inhibition of GSK3α,β rescues cognitive phenotypes in a preclinical mouse model of CTNNB1 syndrome

CTNNB1 syndrome is a rare monogenetic disorder caused by CTNNB1 de novo pathogenic heterozygous loss-of-function variants that result in cognitive and motor disabilities. Treatment is currently lacking; our study addresses this critical need. CTNNB1 encodes beta-catenin which is essential for normal brain function via its dual roles in cadherin-based synaptic adhesion complexes and canonical Wnt signal transduction. We have generated a Ctnnb1 germline heterozygous mouse line that displays cognitive and motor deficits, resembling key features of CTNNB1 syndrome in humans. Compared with wild-type littermates, Ctnnb1 heterozygous mice also exhibit decreases in brain beta-catenin, beta-catenin association with N-cadherin, Wnt target gene expression, and Na/K ATPases, key regulators of changes in ion gradients during high activity. Consistently, hippocampal neuron functional properties and excitability are altered. Most important, we identify a highly selective inhibitor of glycogen synthase kinase (GSK)3 alpha,beta that significantly normalizes the phenotypes to closely meet wild-type littermate levels. Our data provide new insights into brain molecular and functional changes, and the first evidence for an efficacious treatment with therapeutic potential for individuals with CTNNB1 syndrome. CTNNB1 Syndrome is characterized by intellectual and motor disabilities caused by heterozygous loss-of-function pathogenic variants. As the first evidence for a corrective treatment, Ctnnb1 + /- mouse phenotypes resemble the human disorder and are significantly normalized with inhibition of GSK3 alpha,beta.Ctnnb1 heterozygous mice display cognitive and motor phenotypes resembling key features of human CTNNB1 Syndrome.Ctnnb1 heterozygous mice show molecular and functional changes consistent with the behavioral deficits.Treatment with a highly selective, small molecule GSK3 alpha,beta inhibitor corrects the behavioral, functional, and molecular changes in symptomatic heterozygous mice. CTNNB1 Syndrome is characterized by intellectual and motor disabilities caused by heterozygous loss-of-function pathogenic variants. As the first evidence for a corrective treatment, Ctnnb1 + /- mouse phenotypes resemble the human disorder and are significantly normalized with inhibition of GSK3 alpha,beta.