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Cited by 25Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Albizzati, Elena, Breccia, Martina, Florio, Elena, Cabasino, Cecilia, Postogna, Francesca Maddalena, Grassi, Riccardo, Boda, Enrica, Battaglia, Cristina +5 more·2024·iScience
DOI 10.1016/j.isci.2024.109296PMC PMC10926209
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Abstract

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.

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  • Mecp2 KO astrocytes influence both synaptogenesis and synapse maintenance through release of synaptotoxic molecules and/or reduced secretion of synaptogenic factors.

    “Indeed, through the release of synaptotoxic molecules and/or the reduced secretion of synaptogenic factors, Mecp2 KO astrocytes influence both synaptogenesis and synapse maintenance (Albizzati et al., 2024;Sun et al., 2023).”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Albizzati et al., 2024

    The Results section reports that molecules secreted by Mecp2 KO cortical astrocytes impair synaptogenesis in WT neurons, and the Discussion proposes toxic molecules and/or reduced synaptogenic cues as possible mechanisms. The paper does not establish an effect on the maintenance of existing synapses, so that part of the claim is unsupported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • RTT astrocytes have a defective capacity to support synaptogenesis and synaptic functionality.

    “Considering the defective capacity of RTT astrocytes to support synaptogenesis and synaptic functionality (Albizzati et al., 2024;Sun et al., 2023), we characterized cholesterol metabolism in Mecp2 deficient astrocytes.”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Albizzati et al., 2024

  • Mecp2 deficient astrocytes secrete excessive interleukin-6, leading to reduced synapse density and impaired synaptic function in wild-type neurons.

    “We recently demonstrated that Mecp2 deficient astrocytes secrete excessive amounts of interleukin-6 (IL-6), leading to reduced synapse density and impaired synaptic function in wild-type (WT) neurons (Albizzati et al., 2024).”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Albizzati et al., 2024

  • MECP2 mutant astrocytes contribute to neuronal alterations through non-cell-autonomous mechanisms.

    “and MECP2 mutant astrocytes contribute to neuronal alterations through non-cell-autonomous mechanisms (Albizzati et al., 2024;Ballas et al., 2009;Sun et al., 2023;Williams et al., 2014).”

    From Impaired astrocyte-to-neuron cholesterol trafficking drives synaptic dysfunction in Rett syndrome (2026) · cites this paper as Albizzati et al., 2024

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Cited by

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Authors
Albizzati, E., Breccia, M., Florio, E., Cabasino, C., Postogna, F. M., Grassi, R., Boda, E., Battaglia, C., De Palma, C., De Quattro, C., Pozzi, D., Landsberger, N., & Frasca, A.
Affiliations
  • University of Milan (IT)
  • Humanitas University (IT)
  • Neuroscience Institute Cavalieri Ottolenghi (IT)
Corresponding author
Frasca, Angelisa
ORCID
Venue
iScience
Publisher
Elsevier BV
Published
2024-03
Volume
27
Issue
3
Pages
109296
ISSN
2589-0042 (ISSN-L)
DOI
10.1016/j.isci.2024.109296
PMC
PMC10926209
OpenAlex
W4392123619
Cited by
25
References
6
Citations by year
2026: 11 · 2025: 9 · 2024: 5
FWCI
6.63
Type
journal article
Language
en
Open access
Licence
Locations
  • iScience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Università degli Studi di Milano
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
MeCP2, astrocytes, synaptogenesis, interleukin-6, astrocyte-neuron crosstalk

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