P2X7 receptors drive poly(I:C) induced autism-like behavior in mice

Gergely Horváth, Lilla Otrokocsi, Katinka Beko, Mária Baranyi, Ágnes Kittel, Pablo Antonio Fritz-Ruenes, Beáta Sperlágh

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2542-2561
Number of pages20
JournalJournal of Neuroscience
Volume39
Issue number13
DOIs
Publication statusPublished - Mar 27 2019

Keywords

  • ASD
  • ATP
  • JNJ47965567
  • MIA
  • P2X7
  • Poly(I:C)

ASJC Scopus subject areas

  • Neuroscience(all)

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