P2X7 Receptors Drive Poly(I:C) Induced Autism-like Behavior in Mice.
Animals
Autism Spectrum Disorder
/ chemically induced
Cerebellum
/ ultrastructure
Cytokines
/ immunology
Disease Models, Animal
Female
Male
Mice, Inbred C57BL
Mice, Knockout
Poly I-C
/ administration & dosage
Pregnancy
Prenatal Exposure Delayed Effects
/ immunology
Receptors, Purinergic P2X7
/ genetics
ASD
ATP
JNJ47965567
MIA
P2X7
poly(I:C)
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
ISSN: 1529-2401
Titre abrégé: J Neurosci
Pays: United States
ID NLM: 8102140
Informations de publication
Date de publication:
27 03 2019
27 03 2019
Historique:
received:
24
07
2018
revised:
09
01
2019
accepted:
12
01
2019
pubmed:
27
1
2019
medline:
19
3
2020
entrez:
27
1
2019
Statut:
ppublish
Résumé
Maternal immune activation (MIA) is a principal environmental risk factor contributing to autism spectrum disorder (ASD), which compromises fetal brain development at critical periods of pregnancy and might be causally linked to ASD symptoms. We report that endogenous activation of the purinergic ion channel P2X7 (P2rx7) is necessary and sufficient to transduce MIA to autistic phenotype in male offspring. MIA induced by poly(I:C) injections to P2rx7 WT mouse dams elicited an autism-like phenotype in their offspring, and these alterations were not observed in P2rx7-deficient mice, or following maternal treatment with a specific P2rx7 antagonist, JNJ47965567. Genetic deletion and pharmacological inhibition of maternal P2rx7s also counteracted the induction of IL-6 in the maternal plasma and fetal brain, and disrupted brain development, whereas postnatal P2rx7 inhibition alleviated behavioral and morphological alterations in the offspring. Administration of ATP to P2rx7 WT dams also evoked autistic phenotype, but not in KO dams, implying that P2rx7 activation by ATP is sufficient to induce autism-like features in offspring. Our results point to maternal and offspring P2rx7s as potential therapeutic targets for the early prevention and treatment of ASD.
Identifiants
pubmed: 30683682
pii: JNEUROSCI.1895-18.2019
doi: 10.1523/JNEUROSCI.1895-18.2019
pmc: PMC6435822
doi:
Substances chimiques
Cytokines
0
P2rx7 protein, mouse
0
Receptors, Purinergic P2X7
0
Poly I-C
O84C90HH2L
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2542-2561Informations de copyright
Copyright © 2019 the authors 0270-6474/19/392542-20$15.00/0.
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