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Title

Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism

Authors
Jiang, Yong-Hui
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Published in Molecular psychiatry. 2022, vol. 27, no. 4, p. 2080-2094
Abstract Mutations in the SHANK3 gene have been recognized as a genetic risk factor for Autism Spectrum Disorder (ASD), a neurodevelopmental disease characterized by social deficits and repetitive behaviors. While heterozygous SHANK3 mutations are usually the types of mutations associated with idiopathic autism in patients, heterozygous deletion of Shank3 gene in mice does not commonly induce ASD-related behavioral deficit. Here, we used in-vivo and ex-vivo approaches to demonstrate that region-specific neonatal downregulation of Shank3 in the Nucleus Accumbens promotes D1R-medium spiny neurons (D1R-MSNs) hyperexcitability and upregulates Transient Receptor Potential Vanilloid 4 (Trpv4) to impair social behavior. Interestingly, genetically vulnerable Shank3+/-mice, when challenged with Lipopolysaccharide to induce an acute inflammatory response, showed similar circuit and behavioral alterations that were rescued by acute Trpv4 inhibition. Altogether our data demonstrate shared molecular and circuit mechanisms between ASD-relevant genetic alterations and environmental insults, which ultimately lead to sociability dysfunctions.
Keywords Autism Spectrum Disorder / geneticsDisease Models, AnimalNerve Tissue Proteins / geneticsSocial Behavior
Identifiers
PMID: 35022531
PMCID: PMC9126815
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Structures
Research groups Neurobiologie développementale et plasticité (880)
Les dysfonctions synaptiques du cerveau (971)
NCCR Synapsy
Citation
(ISO format)
TZANOULINOU, Stamatina et al. Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism. In: Molecular psychiatry, 2022, vol. 27, n° 4, p. 2080-2094. doi: 10.1038/s41380-021-01427-0 https://archive-ouverte.unige.ch/unige:163455

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Deposited on : 2022-09-21

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