Fragile X (FX) is the most common genetic cause of
intellectual disability and
autism. Previous studies have shown that partial inhibition of
metabotropic glutamate receptor signaling is sufficient to correct behavioral phenotypes in a mouse model of FX, including audiogenic
seizures, open-field hyperactivity and social behavior. These phenotypes model well the
epilepsy (15%), hyperactivity (20%) and
autism (30%) that are comorbid with FX in human patients. Identifying reliable and robust mouse phenotypes to model
cognitive impairments is critical considering the 90% comorbidity of FX and
intellectual disability. Recent work characterized a five-choice visuospatial discrimination assay testing cognitive flexibility, in which FX model mice show impairments associated with decreases in synaptic
proteins in prefrontal cortex (PFC). In this study, we sought to determine whether instrumental extinction, another process requiring PFC, is altered in FX model mice, and whether downregulation of
metabotropic glutamate receptor signaling pathways is sufficient to correct both visuospatial discrimination and extinction phenotypes. We report that instrumental extinction is consistently exaggerated in FX model mice. However, neither the extinction phenotype nor the visuospatial discrimination phenotype is corrected by approaches targeting
metabotropic glutamate receptor signaling. This work describes a novel behavioral extinction assay to model impaired cognition in mouse models of
neurodevelopmental disorders, provides evidence that extinction is exaggerated in the FX mouse model and suggests possible limitations of
metabotropic glutamate receptor-based
pharmacotherapy.