Synaptic abnormalities represent a hallmark for several neurological diseases and clarification of the underlying mechanisms constitutes a crucial step towards the development of therapeutic strategies. Rett syndrome (RTT) is a rare neurodevelopmental disorder, mainly affecting females, caused by heterozygous mutations in the X-linked Methyl-CpG-Binding Protein 2 (MECP2) gene, leading to a deep derangement of synaptic connectivity. Although initial studies have supported the exclusive involvement of neurons, recent data have highlighted the pivotal contribution of astrocytes in RTT pathogenesis through non-cell autonomous mechanisms. Since astrocytes regulate synaptogenesis by releasing multiple molecules, we investigated the influence of soluble factors secreted byMecp2KO astrocytes on synaptic density. We found thatMecp2deficiency in astrocytes negatively affects their ability to support synapse formation by releasing synaptotoxic molecules, among which we identified interleukin-6 (IL-6). Notably, aberrant IL-6 expression exclusively emerges from a dysfunctional astrocyte-neuron crosstalk, and blocking IL-6 activity prevents synaptic alterations.
