Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia

• DOI: 10.1523/jneurosci.2469-20.2020
• Publication Date: 2021-01-15T18:50:13Z
• Authors: 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-Co...; Candice Askwith; Jonathan P. Godbout
• Keywords: Cerebral Cortex; Male; Neurons; 0303 health sciences; Long-Term Potentiation; Gene Expression; Motor Activity; 3. Good health; Mice, Inbred C57BL; Mice; 03 medical and health sciences; Suppression, Genetic; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; Brain Injuries, Traumatic; Animals; Encephalitis; Calcium Signaling; Interferons; Microglia; Organic Chemicals; Psychomotor Performance

Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed determine the contribution of microglia neuropathology at acute [1 d postinjury (dpi)], subacute (7 dpi), chronic (30 dpi) time points. Microglia were depleted with PLX5622, a CSF1R antagonist, before midline fluid percussion (FPI) in male mice cortical neuropathology/inflammation was assessed using mRNA panel. Gene expression associated inflammation robustly increased acutely (1 majority independent. At 7 30 dpi, however, microglial depletion reversed TBI-related genes inflammation, interferon signaling, neuropathology. Myriad suppressed endpoints attributed neurons. To understand relationship between microglia, neurons, other glia, single-cell RNA sequencing completed critical point evolution from pathogenesis. Cortical exhibited distinct TBI-associated clustering type-1 neurodegenerative/damage-related genes. In dopamine long-term potentiation, calcium synaptogenesis suppressed. Microglial these neuronal alterations. Furthermore, there reduced dendritic complexity connectively cognitive impairment dpi. All functional behavioral impairments prevented by depletion. Collectively, studies indicate that promote persistent homeostasis TBI.SIGNIFICANCE STATEMENT Millions traumatic injuries (TBIs) occur United States alone each year. Survivors face elevated rates psychiatric complications long inciting Recent human link neuroinflammation adverse neurologic outcomes, suggesting evolving inflammatory may be an opportunity for intervention. Here, eliminate compare effects diffuse TBI on neurons presence absence microglia-mediated inflammation. do not undergo TBI-induced changes gene transcription or structure. elimination (dpi). have role disrupting TBI, particularly timepoints.