Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome

Significance Cutaneous sensitivity appears to be abnormal in Rett syndrome and other autistic disorders. Using rats with disrupted methyl-CpG binding protein 2 (MeCP2) expression characteristic of Rett syndrome, we found that MeCP2 deficiency in sensory neurons led to augmented pressure and cold sensitivity but hyposensitivity to heat, accompanied by respective changes in cutaneous innervation. Transcriptome analysis of MeCP2-deficient ganglia showed up-regulation of genes associated with actin cytoskeletal dynamics and adhesion formation; down-regulating key genes in vivo normalized both mechanical sensitivity and innervation density. These findings provide evidence that ganglion cytoskeletal genes play key roles in determining mechanosensory properties, which may contribute to altered pain sensitivity in Rett syndrome and other painful conditions.