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

Details

Serval ID
serval:BIB_4F9DF43BEEE8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Inhibition of Trpv4 rescues circuit and social deficits unmasked by acute inflammatory response in a Shank3 mouse model of Autism.
Journal
Molecular psychiatry
Author(s)
Tzanoulinou S., Musardo S., Contestabile A., Bariselli S., Casarotto G., Magrinelli E., Jiang Y.H., Jabaudon D., Bellone C.
ISSN
1476-5578 (Electronic)
ISSN-L
1359-4184
Publication state
Published
Issued date
04/2022
Peer-reviewed
Oui
Volume
27
Number
4
Pages
2080-2094
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
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 <sup>+/-</sup> 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
Animals, Autism Spectrum Disorder/genetics, Autistic Disorder/genetics, Disease Models, Animal, Humans, Mice, Microfilament Proteins/genetics, Nerve Tissue Proteins/genetics, Nerve Tissue Proteins/metabolism, Social Behavior, TRPV Cation Channels/genetics
Pubmed
Web of science
Open Access
Yes
Create date
25/01/2022 7:29
Last modification date
19/12/2023 7:15
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