070 – Diffuse TBI causes Microglia-Dependent Neuronal Dysfunction and Impaired Axonal Conduction

Printed Poster | Session 1

070 – Diffuse TBI causes Microglia-Dependent Neuronal Dysfunction and Impaired Axonal Conduction

Chelsea Bray (1) – Kristina Witcher (1) – Fangli Zhao (1) – Alan Gordillo (1) – Daniel McKim (2) – Xiaoyu Liu (3) – Julia Dziabis (4) – Ning Quan (3) – Candice Askwith (1) – Olga Kokiko-Cochran (1) – Daniel Eiferman (1) – Jonathan Godbout (1)
The Ohio State University, Neuroscience, Columbus, United States (1) – University of Illinois – Urbana Champaign, Neuroscience, Urbana, United States (2) – Florida Atlantic University, Neuroscience, Boca Raton, United States (3) – Duke University, Neuroscience, Durham, United States (4)


Traumatic brain injury (TBI) elicits immediate neuroinflammatory events that cause functional disturbances. Despite resolution of acute complications, chronic impairments may develop after injury. We previously identified microglia as mediators of inflammatory/immune signaling that persisted sub-acutely following diffuse TBI. It was unclear, however, if persistent microglial activation acted as reparative or neurodegenerative. Therefore, electrophysiological, histological, and transcriptome analyses were used to determine microglial contribution to neuropathology (with/without PLX5622-mediated microglial depletion) at acute (1dpi), subacute (7dpi), and chronic (30dpi) time-points. Microglia were eliminated prior to midline fluid perfusion injury and axon conduction and cortical neuropathology/inflammation was assessed. There was a persistent reduction in N2/N1 amplitude of compound action potentials in the corpus callosum 30 dpi. This TBI-associated impairment at 30 dpi was reversed by microglial elimination. To quantify cortical gene expression, Nanostring’s Neuropathology gene expression assay (760 genes) was used. Novel data revealed robust increases in genes associated with inflammation and neuropathology acutely (1 dpi) and a majority of the neuronal damage associated genes (Hmox1, Hsbp1, Fas) were microglia-independent. At 7 and 30 dpi, microglial elimination reversed TBI-related inflammatory gene expression (Itgax, Cd14, Clec7a) and neuropathology (Serpinf1). Sub-acute and chronic suppression of neuronal genes after injury were restored by microglial elimination (Ngf, Trpv1, Drd1, Drd2, Avp). To understand how cell types were influenced by TBI and continual microglia activation we used single cell sequencing. At 7dpi cortical microglia revealed a unique neurodegenerative signature not present in uninjured controls. These injury-associated microglia underwent transcriptional changes consistent with debris clearance. Furthermore, dendritic spine analysis indicates dendritic remodeling is microglia dependent following injury. Thus, microglia promote persistent neuropathological, transcriptional, and functional impairment after diffuse TBI.