Traumatic brain injury causes chronic cortical inflammation and neuronal dysfunction mediated by Microglia

Kristina G. Witcher, Chelsea E. Bray, Titikorn Chunchai, Fangli Zhao, Shane M. O'Neil, Alan J. Gordillo, Warren A. Campbell, Daniel B. McKim, Xiaoyu Liu, Julia E. Dziabis, Ning Quan, Daniel S. Eiferman, Andy J. Fischer, Olga N. Kokiko-Cochran, Candice Askwith, Jonathan P. Godbout

Research output: Contribution to journalArticlepeer-review

Abstract

Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop and persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed to determine the contribution of microglia to neuropathology at acute [1 d postinjury (dpi)], subacute (7 dpi), and chronic (30 dpi) time points. Microglia were depleted with PLX5622, a CSF1R antagonist, before midline fluid percussion injury (FPI) in male mice and cortical neuropathology/inflammation was assessed using a neuropathology mRNA panel. Gene expression associated with inflammation and neuropathology were robustly increased acutely after injury (1 dpi) and the majority of this expression was microglia independent. At 7 and 30 dpi, however, microglial depletion reversed TBI-related expression of genes associated with inflammation, interferon signaling, and neuropathology. Myriad suppressed genes at subacute and chronic endpoints were attributed to neurons. To understand the relationship between microglia, neurons, and other glia, single-cell RNA sequencing was completed 7 dpi, a critical time point in the evolution from acute to chronic pathogenesis. Cortical microglia exhibited distinct TBI-associated clustering with increased type-1 interferon and neurodegenerative/damage-related genes. In cortical neurons, genes associated with dopamine signaling, long-term potentiation, calcium signaling, and synaptogenesis were suppressed. Microglial depletion reversed the majority of these neuronal alterations. Furthermore, there was reduced cortical dendritic complexity 7 dpi, reduced neuronal connectively 30 dpi, and cognitive impairment 30 dpi. All of these TBI-associated functional and behavioral impairments were prevented by microglial depletion. Collectively, these studies indicate that microglia promote persistent neuropathology and long-term functional impairments in neuronal homeostasis after TBI.

Original languageEnglish (US)
Pages (from-to)1597-1616
Number of pages20
JournalJournal of Neuroscience
Volume41
Issue number7
DOIs
StatePublished - Jan 17 2021

Keywords

  • CSF1R antagonist
  • Microglia
  • Neuroinflammation
  • Neurotrauma
  • Traumatic brain injury

ASJC Scopus subject areas

  • General Neuroscience

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