Motor, Somatosensory, Viscerosensory and Metabolic Impairments in a Heterozygous Female Rat Model of Rett Syndrome

Abstract

Rett Syndrome (RTT), an autism-related disorder caused by mutation of the X-linked Methyl CpG-binding Protein 2 (MECP2) gene, is characterized by severe cognitive and intellectual deficits. While cognitive deficits are well-documented in humans and rodent models, impairments of sensory, motor and metabolic functions also occur but remain poorly understood. To better understand non-cognitive deficits in RTT, we studied female rats heterozygous for Mecp2 mutation (Mecp2−/x); unlike commonly used male Mecp2−/y rodent models, this more closely approximates human RTT where males rarely survive. Mecp2−/x rats showed rapid, progressive decline of motor coordination through six months of age as assessed by rotarod performance, accompanied by deficits in gait and posture. Mecp2−/x rats were hyper-responsive to noxious pressure and cold, but showed visceral hyposensitivity when tested by colorectal distension. Mecp2−/x rats ate less, drank more, and had more body fat resulting in increased weight gain. Our findings reveal an array of progressive non-cognitive deficits in this rat model that are likely to contribute to the compromised quality of life that characterizes RTT.

Protective role of mirtazapine in adult female Mecp2+/− mice and patients with Rett syndrome

“…Mechanical hypersensitivity is an emerging finding in RTT research. Two recent studies showed marked skin hyperinnervation [59], and mechanical hypersensitivity in one male rat model proposed to study RTT, and somatosensory and viscerosensory alteration in female rats of the same model [59,60]. In striking agreement, another study demonstrated increased sensory fiber innervation in skin biopsies from RTT patients [61].…”

Deficits in skilled motor and auditory learning in a rat model of Rett syndrome

“…Previous studies report modest deficits in motor function in Mecp2 heterozygous or KO animal models [3,13,24,26,29,31,32], but these deficits largely fail to replicate the substantial motor dysfunction observed in Rett patients. Given the appearance of deficits on a challenging auditory task, we next sought to characterize acquisition and performance of Mecp2 rats on a skilled forelimb motor task.…”

“…Rats were generated by breeding a Mecp2 heterozygous Sprague-Dawley female with a wild-type Sprague-Dawley male. Female breeders were obtained from Horizon Discovery (SAGE labs), using zinc finger nuclease technology that generated a 71 base pair deletion in exon 4 [3,9,31]. Experimenters were blind to the genotype.…”

“…Initial work successfully modeled psychomotor regression similarly seen in girls with Rett syndrome by using a seed opening task in Mecp2 rats [31]. Other studies using the same rat model have found abnormalities in gait, rotarod performance, and speech discrimination performance [3,9]. It is likely that detailed characterization of other complex behaviors known to be altered in Rett syndrome, such as skilled learning, could expand the utility of these animal models.…”

Rett syndrome from bench to bedside: recent advances

“…Female Mecp2-deficient rats also recapitulated the motor and behavioral phenotype observed in existing mouse models. More recently, two studies published by the Smith lab showed neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in the male rat model and non-cognitive deficits (motor, somatosensory, viscerosensory, and metabolic impairments) in the female rat model 43 , 44 . To date, research using these new rat models has confirmed the observations made in the mouse; it will be interesting to see whether future studies will only replicate and validate results obtained in the mouse or bring new findings specific to the rat.…”