Mecp2 knock-out astrocytes affect synaptogenesis by interleukin 6 dependent mechanisms

Synaptic abnormalities are a hallmark of several neurological diseases, and clarification of the underlying mechanisms represents a crucial step toward the development of therapeutic strategies. Rett syndrome (RTT) is a rare neurodevelopmental disorder, mainly affecting females, caused by mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene, leading to a deep derangement of synaptic connectivity. Although initial studies 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 synapse formation and functionality by releasing multiple molecules, we investigated the influence of soluble factors secreted by Mecp2 knock-out (KO) astrocytes on synapses. We found that Mecp2 deficiency in astrocytes negatively affects their ability to support synaptogenesis by releasing synaptotoxic molecules. Notably, neuronal inputs from a dysfunctional astrocyte-neuron crosstalk lead KO astrocytes to aberrantly express IL-6, and blocking IL-6 activity prevents synaptic alterations. [Display omitted] •High levels of IL-6 secreted by Mecp2 KO astrocytes negatively affect synapses•IL-6 upregulation results from an altered astrocyte-neuron crosstalk in Rett syndrome•Astrocytes from Mecp2 heterozygous mouse cortices express high levels of IL-6 Cell biology; Immunology; Neuroscience; Omics; Transcriptomics