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

Rett syndrome (RTT, online MIM 312750) is a devastating neurodevelopmental disordercharacterized by motor and cognitive disabilities. It is mainly caused by pathogenetic variants in theX-linked MECP2 gene, encoding an epigenetic factor crucial for brain functioning. Despite intensivestudies, the RTT pathogenetic mechanism remains to be fully elucidated. Impaired vascular functionhas been previously reported in RTT mouse models; however, whether an altered brain vascularhomeostasis and the subsequent blood-brain barrier (BBB) breakdown occur in RTT and contribute tothe disease-related cognitive impairment is still unknown. Interestingly, in symptomatic Mecp2-null(Mecp2-/y, Mecp2tm1.1Bird) mice, we found enhanced BBB permeability associated with an aberrantexpression of the tight junction proteins Ocln and Cldn-5 in different brain areas, in terms of bothtranscript and protein levels. Additionally, Mecp2-null mice showed an altered expression of differentgenes encoding factors with a role in the BBB structure and function, such as Cldn3, Cldn12, Mpdz,Jam2, and Aqp4. With this study, we provide the first evidence of impaired BBB integrity in RTT andhighlight a potential new molecular hallmark of the disease that might open new perspectives for thesetting-up of novel therapeutic strategies.