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

Rett syndrome (RTT) is a neurodevelopmental disorder primarily caused by mutations in the X-linked MECP2 gene and affecting 1 in 10,000 girls worldwide. RTT is characterized by several symptoms, including motor dysfunction, respiratory abnormalities and cognitive deficits [1]. Despite extensive research, no cure is available, and treatments remain symptomatic. At the cellular level, RTT is characterized by profound morphological and functional synaptic defects which are in part attributed to non-cell autonomous mechanisms mainly mediated by astrocytes [2,3]. We have demonstrated that Mecp2 knock-out (KO) astrocytes fail to sustain synaptogenesis in WT neurons, and this impairment is associate with an excessive release of interleukin 6 (IL-6). Notably, blocking IL-6 with a neutralizing antibody prevents synaptic alterations, suggesting the possibility to target this cytokine for a therapeutic purpose ]4]. Starting from this evidence, my study aims to extend in vitro findings moving to in vivo validation and exploring IL-6 as a therapeutic target in Mecp2 heterozygous (HET) mice, which better replicate human RTT pathology. We thus analyzed IL-6 expression in the brain of HET animals along the disease progression, finding an increase of the cytokine expression in symptomatic mice. To establish whether IL-6 overexpression is limited to astrocytes that carry the Mecp2 null allele, we took advantage of the Mecp2/EGFP model. This model enables the distinction between Mecp2+ and Mecp2-astrocytes. Further, we started testing whether IL-6 blockade through a neutralizing antibody restores synaptic integrity and improves neurological function in RTT animals. By clarifying IL-6's role in RTT and evaluating its therapeutic potential, this study could pave the way for novel treatments. Targeting astrocyte-driven neuroinflammation may provide a promising strategy to mitigate disease progression and improve patient outcomes.