INVESTIGATING THE ROLE OF DEFECTIVE CELL TO CELL COMMUNICATION MECHANISMS IN RETT SYNDROME PATHOGENESIS
type: CreativeWork
description: Rett syndrome (RTT) is a devastating neurodevelopmental disorder representing the main cause of severe intellectual disability in girls worldwide. Over 95% of individuals suffering from a classic form of RTT carry sporadic mutations in the X-linked MECP2 gene, encoding for the methyl-GpC-binding protein 2 (MeCP2), responsible for the regulation of the expression of thousands of genes. RTT is characterized by defects in neuronal morphology, activity and synaptic transmission, which are in part caused by the insufficient support from astrocytes. Indeed, astrocytes in RTT not only exhibit alterations in their morphology, metabolism and calcium signaling, but they also fail to adequately sustain neuronal growth and activity. Although understanding the causative mechanisms could guide the development of novel and effective therapeutic strategies, they remain largely unknown to date. This study explores the impact of Mecp2 knock-out (KO) astrocytes on synapses, mainly focusing on the paracrine signals, exploiting two different in vitro culture systems. On one hand, we treated neurons with astrocyte conditioned medium (ACM) obtained from wild type (WT) or Mecp2 KO astrocytes. On the other hand, we used a co-culture system between neurons and astrocytes, in which the latter are cultured on transwell inserts preventing the direct contact with neurons while allowing the exchange of secreted molecules. In both the cases, we observed that Mecp2 KO astrocytes severely compromise synaptogenesis and synaptic maintenance, suggesting that they either release synaptotoxic molecules or fail to secrete necessary synaptogenic factors. A transcriptomic study revealed that molecules secreted by Mecp2 KO astrocytes induce an abnormal inflammatory response in neurons, and coherently we found an increase of Interleukin-6 (IL-6) levels in the medium of the co-culture. The excessive amount of IL-6 was proven to be a critical mediator of synaptic defects as its blockade with a specific neutrali…
abstract: Rett syndrome (RTT) is a devastating neurodevelopmental disorder representing the main cause of severe intellectual disability in girls worldwide. Over 95% of individuals suffering from a classic form of RTT carry sporadic mutations in the X-linked MECP2 gene, encoding for the methyl-GpC-binding protein 2 (MeCP2), responsible for the regulation of the expression of thousands of genes. RTT is characterized by defects in neuronal morphology, activity and synaptic transmission, which are in part caused by the insufficient support from astrocytes. Indeed, astrocytes in RTT not only exhibit alterations in their morphology, metabolism and calcium signaling, but they also fail to adequately sustain neuronal growth and activity. Although understanding the causative mechanisms could guide the development of novel and effective therapeutic strategies, they remain largely unknown to date. This study explores the impact of Mecp2 knock-out (KO) astrocytes on synapses, mainly focusing on the paracrine signals, exploiting two different in vitro culture systems. On one hand, we treated neurons with astrocyte conditioned medium (ACM) obtained from wild type (WT) or Mecp2 KO astrocytes. On the other hand, we used a co-culture system between neurons and astrocytes, in which the latter are cultured on transwell inserts preventing the direct contact with neurons while allowing the exchange of secreted molecules. In both the cases, we observed that Mecp2 KO astrocytes severely compromise synaptogenesis and synaptic maintenance, suggesting that they either release synaptotoxic molecules or fail to secrete necessary synaptogenic factors. A transcriptomic study revealed that molecules secreted by Mecp2 KO astrocytes induce an abnormal inflammatory response in neurons, and coherently we found an increase of Interleukin-6 (IL-6) levels in the medium of the co-culture. The excessive amount of IL-6 was proven to be a critical mediator of synaptic defects as its blockade with a specific neutrali…
author: BRECCIA, MARTINA
language: eng
keywords: Rett syndrome, Interleukin-6, cholesterol, astrocyte, neuron, Settore BIOS-08/A - Biologia molecolare, Settore BIOS-10/A - Biologia cellulare e applicata
date published: 2025-01-28
date modified: 2026-07-27T20:19:00Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/1122936

PropertyValue
property ID: DOI
value: 10.13130/breccia-martina_phd2025-01-28