Deficits in forelimb reach learning in a mouse model of Fragile X syndrome

Abstract

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 knockout (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.

Significance statement Rodent models of neurodevelopmental disorders such as Fragile X syndrome are key to understanding how cellular and circuit-level phenomena result in specific behavioral features. As a consequence, detailed and precise characterization of behavioral phenotypes in such mouse models is of critical importance. Here, we characterized to an unprecedented level of detail the deficits in a motor learning task in a mouse model of Fragile X syndrome. In addition, we determined that the specific conditions of the behavioral task can provide an apparent alleviation of learning deficits overall. Our results provide a framework for determining the cellular and circuit deficits underlying these different behavioral features, and identify how specific aspects of the learning deficit depend on the conditions of learning.