Temporal patterns of microglial activation in white matter following experimental mild traumatic brain injury: a systematic literature review

Abstract Mild traumatic brain injuries (mTBIs) are a prevalent form of injury that can result in persistent neurological impairments. Microglial activation has become increasingly recognized as a key process regulating the pathology of white matter in a wide range of brain injury and disease contexts. As white matter damage is known to be a major contributor to the impairments that follow mTBI, microglia have rightfully become a common target of investigation for the development of mTBI therapies and biomarkers. Recent work has demonstrated that the efficacy of microglial manipulation as a therapeutic intervention following injury or disease is highly time-sensitive, emphasizing the importance of advancing our understanding of the dynamics of post-mTBI microglial activation from onset to resolution. Current reporting of microglial activation in experimental studies of mTBI is non-standardized, which has limited our ability to identify concrete patterns of post-mTBI microglial activation over time. In this review, we examine preclinical studies of mTBI that report on microglial activation in white matter regions to summarize our current understanding of these patterns. Specifically, we summarize timecourses of post-mTBI microglial activation in white matter regions of the brain, identify factors that influence this activation, examine the temporal relationship between microglial activation and other post-mTBI assessments, and compare the relative sensitivities of various methods for detecting microglial activation. While the lack of replicated experimental conditions has limited the extent of conclusions that can confidently be drawn, we find that microglia are activated over a wide range of timecourses following mTBI and that microglial activation is a long-lasting outcome of mTBI that may resolve after most typical post-mTBI assessments, with the exception of those measuring oligodendrocyte lineage cell integrity. We identify several understudied parameters of post-mTBI microglial activation in white matter, such as the inclusion of female subjects. This review summarizes our current understanding of the progression of microglial activation in white matter structures following experimental mTBI and offers suggestions for important future research directions

Persistent white matter vulnerability in a mouse model of mild traumatic brain injury

Abstract Background Following one mild traumatic brain injury (mTBI), there is a window of vulnerability during which subsequent mTBIs can cause substantially exacerbated impairments. Currently, there are no known methods to monitor, shorten or mitigate this window. Methods To characterize a preclinical model of this window of vulnerability, we first gave male and female mice one or two high-depth or low-depth mTBIs separated by 1, 7, or 14 days. We assessed brain white matter integrity using silver staining within the corpus callosum and optic tracts, as well as behavioural performance on the Y-maze test and visual cliff test. Results The injuries resulted in windows of white matter vulnerability longer than 2 weeks but produced no behavioural impairments. Notably, this window duration is substantially longer than those reported in any previous preclinical vulnerability study, despite our injury model likely being milder than the ones used in those studies. We also found that sex and impact depth differentially influenced white matter integrity in different white matter regions. Conclusions These results suggest that the experimental window of vulnerability following mTBI may be longer than previously reported. Additionally, this work highlights the value of including white matter damage, sex, and replicable injury models for the study of post-mTBI vulnerability and establishes important groundwork for the investigation of potential vulnerability mechanisms, biomarkers, and therapies

Pannexin-1 opening in neuronal edema causes cell death but also leads to protection via increased microglia contacts

Summary: Neuronal swelling during cytotoxic edema is triggered by Na+ and Cl− entry and is Ca2+ independent. However, the causes of neuronal death during swelling are unknown. Here, we investigate the role of large-conductance Pannexin-1 (Panx1) channels in neuronal death during cytotoxic edema. Panx1 channel inhibitors reduce and delay neuronal death in swelling triggered by voltage-gated Na+ entry with veratridine. Neuronal swelling causes downstream production of reactive oxygen species (ROS) that opens Panx1 channels. We confirm that ROS activates Panx1 currents with whole-cell electrophysiology and find scavenging ROS is neuroprotective. Panx1 opening and subsequent ATP release attract microglial processes to contact swelling neurons. Depleting microglia using the CSF1 receptor antagonist PLX3397 or blocking P2Y12 receptors exacerbates neuronal death, suggesting that the Panx1-ATP-dependent microglia contacts are neuroprotective. We conclude that cytotoxic edema triggers oxidative stress in neurons that opens Panx1 to trigger death but also initiates neuroprotective feedback mediated by microglia contacts