Repetitive mild traumatic brain injury affects inflammation and excitotoxic mRNA expression at acute and chronic time-points

Abstract

The cumulative effect of mild traumatic brain injuries (mTBI) can result in chronic neurological damage, however the molecular mechanisms underpinning this detriment require further investigation. A closed head weight drop model that replicates the biomechanics and head acceleration forces of human mTBI was used to provide an exploration of the acute and chronic outcomes following single and repeated impacts. Adult male C57BL/6J mice were randomly assigned into one of four impact groups (control; one, five and 15 impacts) which were delivered over 23 days. Outcomes were assessed 48 hours and 3 months following the final mTBI. Hippocampal spatial learning and memory assessment revealed impaired performance in the 15-impact group compared with control in the acute phase that persisted at chronic measurement. mRNA analyses were performed on brain tissue samples of the cortex and hippocampus using quantitative RT-PCR. Eight genes were assessed, namely MAPT, GFAP, AIF1, GRIA1, CCL11, TARDBP, TNF, and NEFL, with expression changes observed based on location and follow-up duration. The cortex and hippocampus showed vulnerability to insult, displaying upregulation of key excitotoxicity and inflammation genes. Serum samples showed no difference between groups for proteins phosphorylated tau and GFAP. These data suggest that the cumulative effect of the impacts was sufficient to induce mTBI pathophysiology and clinical features. The genes investigated in this study provide opportunity for further investigation of mTBI-related neuropathology and may provide targets in the development of therapies that help mitigate the effects of mTBI.

Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

“…4B ). Following smTBI, GFAP was reported to marginally increase in the hours after smTBI (61,75,79,83,90), and then return to sham values between 2-7d post-injury (56,60,63). There was an exception in one study using a weight drop injury model that reported increased GFAP levels at 30d post-injury (73).…”

“…There was an exception in one study using a weight drop injury model that reported increased GFAP levels at 30d post-injury (73). In rmTBI models, GFAP was assessed at ’hours’ in 5 studies (42,56,66,81,83), at ’days’ in 3 studies (42,63,93), at ’weeks’ in 2 studies (42,66), and at ’months’ in 3 studies (63,88,92) ( Fig. 4C ).…”

Unraveling the toxic effects mediated by the neurodegenerative disease–associated S375G mutation of TDP-43 and its S375E phosphomimetic variant

“…From a biological point of view, the significance of this finding could be very high because, although rescue of TDP-43 pathology did not occur in a yeast model of disease following ablation of the homologous yeast gene (Aif1p) ( 56 ), elevated levels of this factor have been observed in specific molecular subtypes of ALS patients ( 57 ), in the cortex of mice subjected to mild traumatic brain injury ( 58 ), and very recently in Atxn-CAG100 knock-in mice that eventually develop TDP-43 pathology ( 59 ).…”

Identification of Key Genes and Pathways in the Hippocampus after Traumatic Brain Injury: Bioinformatics Analysis and Experimental Validation

“…Aif1 is a calcium-binding protein that regulates immune and inflammatory responses [58,59]. Increased expression of Aif1 is an indication of microglia and macrophage activation in response to brain trauma [60,61]. A previous experimental study identified Trem2 and Tyrobp as significant hub genes in TBI mice expressing human APOE [62].…”