Hidden Mechanisms Behind Motor Skill Deficits in Down Syndrome
Children with Down syndrome (DS) face a constellation of developmental challenges, including significant deficits in balance and fundamental movement skills. While cerebellar hypoplasia and granule cell loss have been implicated in these motor impairments, the precise mechanisms remain elusive. Previous rodent models have yielded limited insights due to phenotypic drift, microglial overactivation, and mosaicism. However, the advent of MAC21 mice, a novel humanized transchromosomic model, offers an unprecedented opportunity to unravel the intricacies of DS-associated motor deficits.
Our compelling research has uncovered distinct behavioral and anatomical alterations in MAC21 mice, revealing disrupted Purkinje cell connectivity and premature Purkinje cell differentiation. By employing a modified chemogenetic tool, we will meticulously dissect the cellular trafficking pathway associated with primary cilia dysfunction and its impact on motor learning behavior. Our groundbreaking study will provide critical insights into the cerebellar circuitry underlying DS-associated movement adaptation deficits.