Experimental models of Rett syndrome based on Mecp2 dysfunction

Abstract

Rett syndrome (RTT) is a neurodevelopmental disorder predominantly occurring in females with an incidence of 1:10,000 births and caused by sporadic mutations in the MECP2 gene, which encodes methyl-CpG-binding protein-2, an epigenetic transcription factor that binds methylated DNA. The clinical hallmarks include a period of apparently normal early development followed by a plateau and then subsequent frank regression. Impaired visual and aural contact often lead to an initial diagnosis of autism. The characterization of experimental models based on the loss-of-function of the mouse Mecp2 gene revealed that subtle changes in the morphology and function of brain cells and synapses have profound consequences on network activities that underlie critical brain functions. Furthermore, these experimental models have been used for successful reversals of RTT-like symptoms by genetic, pharmacological and environmental manipulations, raising hope for novel therapeutic strategies to improve the quality of life of RTT individuals.

FIGURE 1. Dendritic Spines of Pyramidal Neurons in Rat Hippocampal Slice Cultures and from Human Hippocampus

Upper panels: CA1 pyramidal neurons from human hippocampus stained with DiI by "diolistics" showing marked reduction and aberrant morphology of dendritic spines in samples from child (age 5) and adult (age 21) with RTT, compared to non-MR controls, child (age 3) and adult (age 35), respectively. Lower panels: Rat CA1 neurons (96 hours post-transfection with enhanced yellow fluorescent protein, eYFP) in slice cultures showing an increase in spine density (wildtype MECP2 over-expression) and decrease in spine density (mutant R106W and T158M MECP2 over-expression). Modified with permission from (27).