Female CGG knock-in mice modeling the fragile X premutation are impaired on a skilled forelimb reaching task

Abstract

The fragile X premutation is a tandem CGG trinucleotide repeat expansion in the fragile X mental retardation 1 (FMR1) gene between 55 and 200 repeats in length. A CGG knock-in (CGG KI) mouse has been developed that models the neuropathology and cognitive deficits reported in fragile X premutation carriers. Previous studies have demonstrated that CGG KI mice have spatiotemporal information processing deficits and impaired visuomotor function that worsen with increasing CGG repeat length. Since skilled forelimb reaching requires integration of information from the visual and motor systems, skilled reaching performance could identify potential visuomotor dysfunction in CGG KI mice. To characterize motor deficits associated with the fragile X premutation, 6 month old female CGG KI mice heterozygous for trinucleotide repeats ranging from 70-200 CGG in length were tested for their ability to learn a skilled forelimb reaching task. The results demonstrate that female CGG KI mice show deficits for learning a skilled forelimb reaching task compared to wildtype littermates, and that these deficits worsen with increasing CGG repeat lengths.

Figure 1. CGG repeat length modulates skilled reaching task performance

A. During the first 6 days of learning, all mice performed similarly. After day 7, CGG KI mice show deficits for skilled forelimb reaching compared to wildtype littermate controls (**). Beginning on day 8, the CGG KI mice with 136–200 CGG repeats (High CGG) are impaired relative to CGG KI mice with 70–116 CGG repeats (Low CGG) (#). ** p<.001, # p<.01. B. A Pearson’s correlation coefficient was calculated within CGG KI mice performance during days 12–15 demonstrating an inverse linear association between increasing CGG repeat length and asymptotic performance levels of the skilled reaching task (wildtype mice were excluded from the analysis to focus on mice with expanded CGG repeat lengths; corr = −.63, p_(adj)=.03; R_(adj)² =.44).