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.
Highlights
Autism spectrum disorders (ASDs) and related ASD-like disorders are recognized primarily by cognitive and intellectual deficits
Cognitive deficits such as impaired sociability, anxiety, nest building, contextual fear conditioning, memory function and behavioral regression are prominent in rodent models [7,8,9,10,11,12,13,14], and studies using these Methyl CpG-binding Protein 2 (MECP2) knockout animals have contributed much to our current mechanistic understanding of Rett syndrome (RTT) [15]
This work demonstrates the feasibility of using heterozygous female rats to study progressive non-cognitive pathologies associated with RTT
Summary
Autism spectrum disorders (ASDs) and related ASD-like disorders are recognized primarily by cognitive and intellectual deficits. Rett syndrome (RTT) is one of the most severe autism-like disorders affecting, one in 10,000 female births It is caused by mutation of the X-linked gene MECP2, which is highly expressed in neurons and regulates chromatin organization and global gene transcription [1,2,3]. Intellectual and cognitive defects in RTT have been extensively studied in humans as well as animal models [6] Cognitive deficits such as impaired sociability, anxiety, nest building, contextual fear conditioning, memory function and behavioral regression are prominent in rodent models [7,8,9,10,11,12,13,14], and studies using these MECP2 knockout animals have contributed much to our current mechanistic understanding of RTT [15]
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