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Research Articles, Cellular/Molecular

Elevated TNF-α Leads to Neural Circuit Instability in the Absence of Interferon Regulatory Factor 8

Philip A. Feinberg, Shannon C. Becker, Leeyup Chung, Loris Ferrari, David Stellwagen, Christelle Anaclet, Violeta Durán-Laforet, Travis E. Faust, Rachita K. Sumbria and Dorothy P. Schafer
Journal of Neuroscience 10 August 2022, 42 (32) 6171-6185; DOI: https://doi.org/10.1523/JNEUROSCI.0601-22.2022
Philip A. Feinberg
1Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605
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Shannon C. Becker
1Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605
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Leeyup Chung
1Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605
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Loris Ferrari
1Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605
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David Stellwagen
2Department of Neurology and Neurosurgery, Centre for Research in Neuroscience, Research Institute of the McGill University Health Center, Montreal, Quebec Canada H3G 1A4
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Christelle Anaclet
1Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605
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Violeta Durán-Laforet
1Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605
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Travis E. Faust
1Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605
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Rachita K. Sumbria
3Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, Irvine, California 92618
4Department of Neurology, University of California, Irvine, California 92868
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Dorothy P. Schafer
1Department of Neurobiology, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Chan Medical School, Worcester, Massachusetts 01605
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Abstract

Interferon regulatory factor 8 (IRF8) is a transcription factor necessary for the maturation of microglia, as well as other peripheral immune cells. It also regulates the transition of microglia and other immune cells to a pro-inflammatory phenotype. Irf8 is also a known risk gene for multiple sclerosis and lupus, and it has recently been shown to be downregulated in schizophrenia. While most studies have focused on IRF8-dependent regulation of immune cell function, little is known about how it impacts neural circuits. Here, we show by RNAseq from Irf8−/− male and female mouse brains that several genes involved in regulation of neural activity are dysregulated. We then show that these molecular changes are reflected in heightened neural excitability and a profound increase in susceptibility to lethal seizures in male and female Irf8−/− mice. Finally, we identify that TNF-α is elevated specifically in microglia in the CNS, and genetic or acute pharmacological blockade of TNF-α in the Irf8−/− CNS rescued the seizure phenotype. These results provide important insights into the consequences of IRF8 signaling and TNF-α on neural circuits. Our data further suggest that neuronal function is impacted by loss of IRF8, a factor involved in neuropsychiatric and neurodegenerative diseases.

SIGNIFICANCE STATEMENT Here, we identify a previously unknown and key role for interferon regulator factor 8 (IRF8) in regulating neural excitability and seizures. We further determine that these effects on neural circuits are through elevated TNF-α in the CNS. As IRF8 has most widely been studied in the context of regulating the development and inflammatory signaling in microglia and other immune cells, we have uncovered a novel function. Further, IRF8 is a risk gene for multiple sclerosis and lupus, IRF8 is dysregulated in schizophrenia, and elevated TNF-α has been identified in a multitude of neurologic conditions. Thus, elucidating these IRF8 and TNF-α-dependent effects on brain circuit function has profound implications for understanding underlying, therapeutically relevant mechanisms of disease.

  • IRF8
  • microglia
  • neural-immune
  • seizures
  • synapses
  • TNF alpha

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The Journal of Neuroscience: 42 (32)
Journal of Neuroscience
Vol. 42, Issue 32
10 Aug 2022
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Elevated TNF-α Leads to Neural Circuit Instability in the Absence of Interferon Regulatory Factor 8
Philip A. Feinberg, Shannon C. Becker, Leeyup Chung, Loris Ferrari, David Stellwagen, Christelle Anaclet, Violeta Durán-Laforet, Travis E. Faust, Rachita K. Sumbria, Dorothy P. Schafer
Journal of Neuroscience 10 August 2022, 42 (32) 6171-6185; DOI: 10.1523/JNEUROSCI.0601-22.2022

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Elevated TNF-α Leads to Neural Circuit Instability in the Absence of Interferon Regulatory Factor 8
Philip A. Feinberg, Shannon C. Becker, Leeyup Chung, Loris Ferrari, David Stellwagen, Christelle Anaclet, Violeta Durán-Laforet, Travis E. Faust, Rachita K. Sumbria, Dorothy P. Schafer
Journal of Neuroscience 10 August 2022, 42 (32) 6171-6185; DOI: 10.1523/JNEUROSCI.0601-22.2022
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Keywords

  • IRF8
  • microglia
  • neural-immune
  • Seizures
  • synapses
  • TNF alpha

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