The maternal immune activation model uncovers a role for the Arx gene in GABAergic dysfunction in schizophrenia

Jay P. Nakamura, Anna Schroeder, Matthew Hudson, Nigel Jones, Brendan Gillespie, Xin Du, Michael Notaras, Vaidy Swaminathan, William R. Reay, Joshua R. Atkins, Melissa J. Green, Vaughan J. Carr, Murray J. Cairns, Suresh Sundram, Rachel A. Hill

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

A hallmark feature of schizophrenia is altered high frequency neural oscillations, including reduced auditory-evoked gamma oscillatory power, which is underpinned by parvalbumin (PV) interneuron dysfunction. Maternal immune activation (MIA) in rodents models an environmental risk factor for schizophrenia and recapitulates these PV interneuron changes. This study sought to link reduced PV expression in the MIA model with alterations to auditory-evoked gamma oscillations and transcript expression. We further aligned transcriptional findings from the animal model with human genome sequencing data. We show that MIA, induced by the viral mimetic, poly-I:C in C57Bl/6 mice, caused in adult offspring reduced auditory-evoked gamma and theta oscillatory power paralleled by reduced PV protein levels. We then showed the Arx gene, critical to healthy neurodevelopment of PV interneurons, is reduced in the forebrain of MIA exposed mice. Finally, in a whole-genome sequenced patient cohort, we identified a novel missense mutation of ARX in a patient with schizophrenia and in the Psychiatric Genomics Consortium 2 cohort, a nominal association of proximal ARX SNPs with the disorder. This suggests MIA, as a risk factor for schizophrenia, may be influencing Arx expression to induce the GABAergic dysfunction seen in schizophrenia and that the ARX gene may play a role in the prenatal origins of schizophrenia pathophysiology.

Original languageEnglish
Pages (from-to)161-171
Number of pages11
JournalBrain, Behavior, and Immunity
Volume81
DOIs
Publication statusPublished - Oct 2019

Keywords

  • ARX
  • GABAergic interneurons
  • Gamma oscillations
  • Hippocampus
  • Maternal immune activation
  • Parvalbumin
  • Prepulse inhibition
  • Schizophrenia
  • Somatostatin
  • Theta oscillations

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