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Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits

ABSTRACT: Fragile X syndrome (FXS) is a monogenic (gene = Fmr1) neurodevelopmental disorder with complex and variable manifestations spanning molecular, neuroanatomical, and behavioral changes. Prior work shows astrocytes and their secreted proteins may contribute to the pathophysiology of FXS, and that the bone morphogenetic protein (BMP) pathway may underlie some of these changes. A conditional knock out (KO) of Smad4 in astrocytes suppresses BMP signaling and lessens the severity of Fmr1 KO audiogenic seizures. Using in vivo transcriptomic and proteomic profiling of astrocytes in the mouse cortex, we find hypermetabolic gene expression programs and downregulated secretory machinery and secreted proteins in Fmr1 KO astrocytes that are moderated by Smad4 cKO. Critically, astrocyte Smad4 conditional KO restores deficits in Fmr1 KO auditory cortex inhibitory synaptic density. Thus, astrocytes can contribute to Fmr1 KO molecular and functional phenotypes, and targeting astrocytes can mitigate FXS symptoms.

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Nicola J. Allen

PROVIDER: MSV000094549 | MassIVE | Mon Apr 15 21:58:00 BST 2024

SECONDARY ACCESSION(S): PXD051469

REPOSITORIES: MassIVE

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Project description:Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of co-morbidity with autism spectrum disorders. Several lines of evidences suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. We utilized mouse models of these monogenic disorders to identify genome-wide transcriptional changes in cerebellum and blood and characterize the (dis-)similarity of their molecular signatures. Differentially expressed genes and enriched pathways were distinct for the two mouse models examined, with the exception of immune system related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both blood and brain of Fmr1-KO mice. In both the blood and brain of the Tsc2 heterozygous mouse model, immune system related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly perturbed. Our data suggest that distinct molecular pathways may be involved in autism spectrum disorders with known but different genetic causes, and that blood gene expression profiles of Fmr1-knockout and Tsc2+/- mice mirror some, but not all, of the perturbed molecular pathways in the brain. For the Fmr1-KO model, 10 mice, consisting of 5 KO and 5 WT mice, were profiled. Thus, 10 pairs of blood and cerebella samples were profiled. Likewise, for the Tsc+/- model, 3 transgenic and 3 WT mice were sacrificed and paired blood and cerebella samples were prepared for gene expression profiling. All samples were profiled using the Affymetrix Mouse Gene ST 1.0 ST arrays. Three factors—tissue (i.e. blood vs. cerebellum), treatment (i.e. knockout vs. wildtype), and genetic background (Fmr1-KO vs. Tsc2+/-)—were analyzed with analysis of variance (ANOVA). Subsequently, we compared blood and brain gene expression changes in Fmr1 and Tsc2 knockout mice models using WT littermates as controls using t-tests with unequal variances. The false discovery rate (FDR) was calculated using Storey and Tibshirani’s method.

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Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits

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