Role of IL-6 in Rett syndrome: from in vitro findings to in vivo therapeutic target validation

Rett syndrome (RTT) is a rare neurodevelopmental disorder primarily caused by mutations in the X-linked MECP2 gene and it is characterized by severe cognitive deficits and motor dysfunction. Despite extensive research, no cure is available, and treatments remain symptomatic. RTT is characterized by synaptic defects which are in part attributed to non-cell autonomous mechanisms mainly mediated by astrocytes. Through an in vitro approach, we demonstrated that Mecp2 knock-out astrocytes fail to sustain synaptogenesis in WT neurons through an excessive release of interleukin 6 (IL-6). Blocking IL-6 with a neutralizing antibody prevents synaptic alterations, suggesting the possibility to target this cytokine for a therapeutic purpose. My study aims to extend in vitro findings moving to in vivo validation in Mecp2 heterozygous (HET) mice. By analyzing IL-6 expression in HET brains, which are a mosaic of Mecp2+ and Mecp2- cells, we found an increase of the cytokine expression in symptomatic mice. To establish whether IL-6 overexpression is limited to Mecp2- cells, we took advantage of the Mecp2/EGFP model, reporting a selective IL-6 increase in null cells. Further, we tested the in vivo efficacy of a neutralizing antibody against IL-6 in restoring synaptic integrity and neurological functions. By clarifying IL-6's role in RTT and evaluating its therapeutic potential, this study could pave the way for novel treatments.