Albizzati Elena, Breccia Martina, Florio Elena, Cabasino Cecilia, Postogna Francesca Maddalena, Grassi Riccardo, Boda Enrica, Battaglia Cristina, De Palma Clara, De Quattro Concetta, Pozzi Davide, Landsberger Nicoletta, Frasca Angelisa
Department of Medical Biotechnology and Translational Medicine, University of Milan, via F.lli Cervi 93, 20054 Segrate, Milan, Italy.
Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.
iScience. 2024 Feb 23;27(3):109296. doi: 10.1016/j.isci.2024.109296. eCollection 2024 Mar 15.
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 () 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 knock-out (KO) astrocytes on synapses. We found that 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.
突触异常是几种神经疾病的标志，阐明其潜在机制是开发治疗策略的关键一步。雷特综合征（RTT）是一种罕见的神经发育障碍，主要影响女性，由X连锁甲基化CpG结合蛋白2（）基因突变引起，导致突触连接严重紊乱。尽管最初的研究支持神经元的唯一参与，但最近的数据通过非细胞自主机制突出了星形胶质细胞在RTT发病机制中的关键作用。由于星形胶质细胞通过释放多种分子来调节突触形成和功能，我们研究了敲除（KO）星形胶质细胞分泌的可溶性因子对突触的影响。我们发现星形胶质细胞中的缺陷会通过释放突触毒性分子对其支持突触发生的能力产生负面影响。值得注意的是，功能失调的星形胶质细胞-神经元串扰产生的神经元输入导致KO星形胶质细胞异常表达IL-6，而阻断IL-6活性可防止突触改变。
