Blood-Brain Barrier Integrity Is Perturbed in a Mecp2-Null Mouse Model of Rett Syndrome.

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Rett syndrome (RTT) is a neurodevelopmental disorder caused by MECP2 gene variants.
• The exact pathogenic mechanisms of RTT, particularly concerning brain vascular function, are not fully understood.
• Previous studies suggested vascular dysfunction in RTT mouse models, but BBB integrity in RTT remained unclear.

Purpose of the Study:

• To investigate whether altered brain vascular homeostasis and blood-brain barrier (BBB) breakdown occur in RTT.
• To determine if BBB dysfunction contributes to cognitive impairment in RTT.
• To identify potential molecular markers associated with BBB changes in RTT.

Main Methods:

• Analysis of symptomatic Mecp2-null mice.
• Assessment of blood-brain barrier (BBB) permeability.
• Evaluation of tight junction protein expression (Ocln, Cldn-5) at transcript and protein levels.
• Gene expression analysis of factors involved in BBB structure and function (Cldn3, Cldn12, Mpdz, Jam2, Aqp4).

Main Results:

• Enhanced BBB permeability was observed in Mecp2-null mice.
• Aberrant expression of tight junction proteins Ocln and Cldn-5 was found in various brain regions.
• Altered expression of genes crucial for BBB integrity, including Cldn3, Cldn12, Mpdz, Jam2, and Aqp4, was detected.

Conclusions:

• This study provides the first evidence of impaired BBB integrity in Rett syndrome.
• Aberrant expression of tight junction proteins and BBB-related genes suggests a novel molecular hallmark for RTT.
• These findings may open new avenues for developing therapeutic strategies for RTT.