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Scientific article
Open access
English

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

Published inMolecular psychiatry, vol. 27, no. 4, p. 2080-2094
Publication date2022-04
First online date2022-01-12
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.

eng
Keywords
  • Autism Spectrum Disorder / genetics
  • Disease Models, Animal
  • Nerve Tissue Proteins / genetics
  • Social Behavior
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
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Identifiers
ISSN of the journal1359-4184
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