Investigating mouse motor coordination using quantitative trait locus analysis to model the genetic underpinnings of developmental coordination disorder

Abstract

The fundamental skills for motor coordination and motor control emerge through development, from infancy to late childhood years. Neurodevelopmental disorders such as Developmental Coordination Disorder (DCD) lead to impaired acquisition of motor skills. This study investigated motor behaviors that reflect the core symptoms of human DCD through the use of BXD recombinant inbred lines of mice that are known to have divergent phenotypes in many behavioral traits, including motor activity. We sought to correlate behavior in basic motor control tasks with the known genotypes of these reference populations of mice using quantitative trait locus (QTL) mapping. We used twelve BXD lines with an average of 16 mice per group to assess the onset of reflexes during the early neonatal stage of life and differences in motor coordination using the open field, rotarod, and gait analyses during the adolescent/young adulthood period. Results indicated significant variability between lines in as to when neonatal reflexes appeared as well as significant line differences for all measures of motor coordination. Five lines (BXD15, BXD27, BXD28, BXD75, and BXD86) struggled with sensorimotor coordination as seen in gait analysis, rotarod, and open field, similar to human presentation of DCD. We identified three significant quantitative trait loci for gait on proximal Chr 3, Chr 4 and distal Chr 6. Based on expression, function, and polymorphism within the mapped QTL intervals, 7 candidate genes (Gpr63, Spata5, Trpc3, Cntn6, Chl1, Grm7 and Ogg1) emerged. This study offers new insights into mouse motor behavior which promises to be a first murine model to explore the genetics and neural correlates of DCD.

Pathogenetic Insights in Developmental Coordination Disorder Reveal Substantial Overlap with Movement Disorders

“…So far, two genome-wide association studies performed in children with phenotypes resembling DCD failed to identify major risk genes for DCD [24,25]. In mice with DCD-like phenotypic traits, a recent quantitative trait locus analysis identified candidate genes correlating with impaired murine gait and coordination [26]. Until now, these findings have not been replicated in patients with DCD [26].…”

“…In mice with DCD-like phenotypic traits, a recent quantitative trait locus analysis identified candidate genes correlating with impaired murine gait and coordination [26]. Until now, these findings have not been replicated in patients with DCD [26]. Therefore, despite the strong indications for genetic underpinnings, comprehensive knowledge about the associated genes and underlying pathogenetic mechanisms of DCD is still lacking.…”