Wild-type MECP2 expression coincides with age-dependent sensory phenotypes in a female mouse model for Rett syndrome

Area of Science:

• Neuroscience
• Developmental Biology
• Genetics

Background:

• Rett syndrome involves motor and speech regression in girls, linked to MECP2 protein loss.
• Mechanisms driving regression from typical development remain unclear.
• Female Rett syndrome models (Mecp2 Het) have mosaic wild-type MECP2 expression due to X-chromosome inactivation.

Purpose of the Study:

• To characterize wild-type MECP2 expression in the somatosensory cortex of female Mecp2 Het mice.
• To identify cellular and behavioral metrics for studying regression in a female mouse model.
• To establish timelines for regression linked to MECP2 expression changes.

Main Methods:

• Characterized MECP2 expression in the primary somatosensory cortex of adolescent (6-week-old) and adult (12-week-old) female Mecp2 Het mice and wild-type controls.
• Assessed perineuronal net expression and behavioral phenotypes, including tactile sensory perception and pup retrieval.

Main Results:

• Adolescent Het mice showed increased MECP2 in non-parvalbumin neurons, normal perineuronal nets, mild sensory deficits, and efficient pup retrieval.
• Adult Het mice had MECP2 levels similar to controls, increased perineuronal nets, and significant tactile sensory deficits.
• Identified a temporal correlation between MECP2 expression changes and behavioral regression phenotypes.

Conclusions:

• Established a female mouse model with defined timelines to study Rett syndrome regression.
• Changes in wild-type MECP2 expression correlate with specific behavioral deficits and cellular changes.
• Precocious MECP2 increase may offer temporary compensation, while subsequent inability to further increase leads to regression.