Extinction of an instrumental response: a cognitive behavioral assay in Fmr1 knockout mice

Fragile X is the most common genetic cause of intellectual disability and autism. Previous studies have showed that partial inhibition of metabotropic glutamate receptor signaling is sufficient to correct behavioral phenotypes in a mouse model of Fragile X, including audiogenic seizures, open field hyperactivity, and social behavior. These phenotypes model well the epilepsy (15%), hyperactivity (20%) and autism (30%) that are co-morbid with Fragile X in human patients (Schneider et al., 2009). Identifying reliable and robust mouse phenotypes to model cognitive impairments is critical considering the 90% co-morbidity of Fragile X and intellectual disability. Recent work characterized a five-choice visuospatial discrimination assay testing cognitive flexibility, in which Fragile X model mice show impairments associated with decreases in synaptic proteins in prefrontal cortex (Krueger et al., 2011). In this study, we sought to determine whether instrumental extinction, another process requiring prefrontal cortex, is altered in Fragile X 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 Fragile X 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 Fragile X mouse model, and suggests possible limitations of metabotropic glutamate receptor-based pharmacotherapy.