Deficits in Forelimb Reach Learning in a Mouse Model of Fragile X Syndrome

Fragile X syndrome is a leading cause of intellectual disability and autism spectrum disorder, for which therapies are limited. A mouse model of fragile X syndrome, the Fmr1 knock-out (KO) mouse, has been particularly valuable for interrogating the molecular, cellular, and circuit mechanisms that underlie the neurological deficits seen in this syndrome. Key deficits in fragile X syndrome include impairments in social behaviors, cognition, and motor learning. Given the difficulties in extrapolating complex human behaviors to mouse models, motor behaviors are a particularly tractable form of learning to study in the mouse. We investigated a form of forelimb reach learning in both male and female Fmr1 KO mice, quantifying different parameters of the task using both manual analysis and DeepLabCut-based tracking of reach trajectories. While Fmr1 KO mice show impaired learning overall, our results showed that the presence or absence of a cue that signals reward alleviated some of the deficits. In addition to a single metric of success in learning, we determined the specific parameters of the motor behavior that were responsible for that success or failure. Our findings provide an essential framework for linking specific behavioral impairments in motor learning to the cellular and circuit mechanisms that support them.