Role of interleukin 6 in the pathogenesis of Rett syndrome: focus on astrocyte-neuron crosstalk and its therapeutic implication

Rett syndrome (RTT) is a post-natal, progressive and neurodevelopmental disorder affecting 1:10.000 girls worldwide. RTT is mainly caused by mutations in the Methyl CpG binding protein 2 (MECP2) gene located on the X chromosome, and currently no cure is available. The main morphological RTT hallmark include closely packed neurons and decreased dendritic complexity. In particular, in vitro studies report a significant reduction in the number of functional synapses. Although most studies focused on MECP2 deficiency in neurons as the primary cause for synaptic deficits, recent findings indicated that also astrocytes play a significant role through a non-cell autonomous mechanism. Our recent data reported through an in vitro study that Mecp2 KO astrocytes are unable to support synaptogenesis. This phenomenon might be due to the excessive release of synaptotoxic molecules, among which we have identified interleukin 6 (IL-6). IL-6 levels are increased in the medium of Mecp2 KO astrocytes co-cultured with WT neurons as well as in astrocytes acutely isolated from the cortex of heterozygous (HET) mice. Of note, blocking IL-6 by using a neutralizing anti-IL-6 antibody prevented synaptic alterations. The aim of this study is to provide further evidence of the role of IL-6 in RTT. In order to achieve this, we aim to extend the previous in vitro findings to in vivo validation of IL-6 as a possible therapeutic target in HET mouse model of RTT, that better recapitulate the pathological phenotype. We propose two therapeutic approaches to test whether IL-6 blockade might induce a rescue of synaptic alterations and neurological abnormalities in HET mouse models. One approach concerns the injection of sgp130Fc (Olamkicept), an inhibitor of IL-6 trans-signalling, which is associated with its pro-inflammatory effects. A second approach concerns the administration of a neutralising anti-IL-6 antibody in Mecp2 mutant mice.