Sensory Neuron Development and Skeletal Deficits in Down Syndrome

Abstract

All individuals with Down syndrome (DS) present with low bone mineral density (BMD) and neurodevelopmental delays. Altered skeletal development and homeostasis result in skeletal abnormalities observed in humans with DS and DS mouse models increasing the risk of early onset osteoporosis. Exercise or physical activity increases BMD and decreases the risk of osteoporosis. Reduced sensory nerve function and decreased innervation leads to impaired skeletal development and decreased skeletal adaptation to mechanical loads. We studied the impact of triplicated Hsa-21 orthologues, particularly Dyrk1a, on sensory neuron development, function and skeletal innervation, and skeletal adaptation to mechanical loads in DS-related skeletal phenotypes. We hypothesized that i) triplication of Dyrk1a disrupts communication between bone and peripheral sensory neurons during development leading in impaired skeletal development and adaptation and ii) normalization of Dyrk1a will rescue skeletal deficits associated with DS by restoring morphological and functional deficits of sensory neurons. Neuropeptide calcitonin gene-related peptide (CGRP), found in sensory nerve fibers innervating bone and the periosteum, is released in response to mechanical stimulation and promotes bone formation. Ts65Dn male mice (at 6-weeks) released significantly more CGRP in response to capsaicin stimulation compared to controls. Both Ts65Dn and Dp1Tyb male mice (16-weeks) had decreased sensory neurons in L4 dorsal root ganglion (DRG). There were no differences in sensory or sympathetic innervation in Ts65Dn, while Dp1Tyb male mice had slightly increased sympathetic innervation of the distal femur. Mechanical stimulation was performed in male and female Dp1Tyb and control mice with expected and reduced Dyrk1a copy number in sensory neurons. Loading the left tibiae at 1500 με, but not 1800 με for 4 weeks improved trabecular and cortical architecture in male and female mice across all genotypes. These data suggest that triplicated Hsa-21 orthologues impair sensory neuron development and function, potentially disrupting communication between bone and the sensory nervous system during skeletal development and adaptation. Loading may improve bone architecture in DS mice, but the limited response highlights the need to find optimal strain levels to produce an anabolic response and identify Hsa-21 genes that affect skeletal development.