Glycine Reverses Behavioral Deficits in a Mouse Model for Psychosis With 4 Copies of the Gldc Gene

Abstract

A duplication/triplication copy number variant in the 9p24.1 chromosomal region with the additional gene copies being located on a small supernumerary marker chromosome has been identified in patients with psychosis. Mice genetically engineered to harbor 9p24.1 duplications or triplications have been shown to display schizophrenia-like phenotypes, including deficits in startle habituation, latent inhibition, working memory, and social interaction and a reduction in the dendritic spine density. Genetic fine-mapping traced these phenotypes to a duplication or triplication of the Gldc gene, that is, to the presence of three or four functional copies of the Gldc gene. The enzyme glycine decarboxylase (GLDC) degrades glycine, which is a co-agonist at the NMDA receptor. In mice with 4 copies of Gldc, extracellular glycine concentrations have been reported to be reduced, while total glycine concentrations were unaltered. Here, we tested the hypothesis that chronically administered glycine could revert phenotypic changes observed in mice with 4 copies of Gldc. We found that 1.3 g/kg glycine administered in the drinking water reversed the startle habituation deficit, the spatial working memory deficit in Y-maze, the sociability deficit and the latent inhibition deficit, while it had a minimal effect on the density of dendritic spines. We conclude that oral administration of glycine is sufficient to reverse some of the behavioral deficits in mice with 4 copies of Gldc but has a very limited effect on dendritic spine density.