Deficits in Skilled Motor and Auditory Learning in a Rat Model of Rett Syndrome

Abstract

Background Rett Syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2 . Individuals with Rett Syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett Syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome. Methods We evaluated the acquisition and performance of auditory and motor function on two complex tasks in heterozygous female Mecp2 rats. Animals were trained to perform a speech discrimination task or a skilled forelimb reaching task. Results Our results reveal that Mecp2 rats display slower acquisition and reduced performance on an auditory discrimination task than wild-type (WT) littermates. Similarly, Mecp2 rats exhibit impaired learning rates and worse performance on a skilled forelimb motor task compared to WT. Conclusions Together, these findings illustrate novel deficits in skilled learning consistent with clinical manifestation of Rett syndrome and provide a framework for development of therapeutic strategies to improve these complex behaviors.

Reduced complexity of brain and behavior due to MeCP2 disruption and excessive inhibition

“…We compared four different experimental groups: normal rats (rattus norvegicus, n = 3, weights, Sprague Dawley, Harlan Labs, TX, USA), normal rats with pharmacologically altered inhibition, transgenic RTT rats (n = 4, weights, HET KO, SD-Mecp2tm1sage , Horizon Labs, MO, USA), and RTT rats with pharmacologically altered inhibition. The rat model of RTT we study here has been shown to recapitulate important dysfunctions and behaviors found in RTT humans including impaired motor functions [28][29][30] . Our goal was to quantitatively assess differences in three properties of these four experimental groups: body movements, neural activity, and the neuron-to-body relationship.…”