Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder with X-linked dominant inheritance caused mainly by mutations in the methyl-CpG-binding protein 2 (MECP2) gene. The effects of various Mecp2 mutations have been extensively assessed in mouse models, but none adequately mimic the symptoms and pathological changes of RTT. In this study, we assessed the effects of Mecp2 gene deletion on female rats (Mecp2+/-) and found severe impairments in social behavior [at 8 weeks (w), 12 w, and 23 w of age], motor function [at 16 w and 26 w], and spatial cognition [at 29 w] as well as lower plasma insulin-like growth factor (but not brain-derived neurotrophic factor) and markedly reduced acetylcholine (30%-50%) in multiple brain regions compared to female Mecp2+/+ rats [at 29 w]. Alternatively, changes in brain monoamine levels were relatively small, in contrast to reports on mouse Mecp2 mutants. Female Mecp2-deficient rats express phenotypes resembling RTT and so may provide a robust model for future research on RTT pathobiology and treatment.
Highlights
Rett syndrome (RTT) (OMIM 312750) is an X-linked progressive neurodevelopmental disorder with an incidence of about 1:10,000 among newborn females, making it the second most frequent cause of female mental retardation after Down syndrome [1]
To further explore the pathological progression associated with Mecp2 gene deficiency, we examined differences in spatial learning and memory, histopathology, and regional neurotransmitter levels between wild-type (Mecp2+/+) and Mecp2+/− female rats
We first analyzed the effect of Mecp2 gene deficiency on rat social behaviors at 8, 12, and 23 w
Summary
Rett syndrome (RTT) (OMIM 312750) is an X-linked progressive neurodevelopmental disorder with an incidence of about 1:10,000 among newborn females, making it the second most frequent cause of female mental retardation after Down syndrome [1]. It shortens life expectancy by ~30–40 years in females, while males usually demonstrate early onset and die shortly after birth. Over 300 MECP2 mutations and genomic abnormalities have been documented in RTT patients as well as in other mental health disorders, including intellectual disability, autism spectrum disorder, bipolar disorder, and schizophrenia [6]. Based on these genetic studies, several mouse models with various Mecp mutations have been developed and studied over the past
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