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CRISPR-mediated activation of autism gene restores cortical network excitability via mGluR5 signaling. | LitMetric

AI Article Synopsis

Article Abstract

Many mutations in autism spectrum disorder (ASD) affect a single allele, indicating a key role for gene dosage in ASD susceptibility. Recently, haplo-insufficiency of , the gene encoding the extracellular matrix receptor β3 integrin, was associated with ASD. Accordingly, knockout (KO) mice exhibit autism-like phenotypes. The pathophysiological mechanisms of remain, however, unknown, and the potential of targeting this gene for developing ASD therapies uninvestigated. By combining molecular, biochemical, imaging, and pharmacological analyses, we establish that haplo-insufficiency impairs cortical network excitability by promoting extra-synaptic over synaptic signaling of the metabotropic glutamate receptor mGluR5, which is similarly dysregulated in fragile X syndrome, the most frequent monogenic form of ASD. To assess the therapeutic potential of regulating gene dosage, we implemented CRISPR activation and compared its efficacy with that of a pharmacological rescue strategy for fragile X syndrome. Correction of neuronal haplo-insufficiency by CRISPR activation rebalanced network excitability as effectively as blockade of mGluR5 with the selective antagonist MPEP. Our findings reveal an unexpected functional interaction between two ASD genes, thereby validating the pathogenicity of haplo-insufficiency. Further, they pave the way for exploiting CRISPR activation as gene therapy for normalizing gene dosage and network excitability in ASD.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9382421PMC
http://dx.doi.org/10.1016/j.omtn.2022.07.013DOI Listing

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