Traumatic brain injuries (TBIs) account for the majority of injury-related deaths in the United States with roughly two million TBIs occurring annually. Due to the spectrum of severity and heterogeneity in TBIs, investigation into the secondary injury is necessary in order to formulate an effective treatment. A mechanical consequence of trauma involves dysregulation of the blood–brain barrier (BBB) which contributes to secondary injury and exposure of peripheral components to the brain parenchyma. Recent studies have shed light on the mechanisms of BBB breakdown in TBI including novel intracellular signaling and cell–cell interactions within the BBB niche. The current review provides an overview of the BBB, novel detection methods for disruption, and the cellular and molecular mechanisms implicated in regulating its stability following TBI.

Circulating monocytes have emerged as key regulators of the neuroinflammatory milieu in a number of neuropathological disorders. Ephrin type-A receptor 4 (Epha4) receptor tyrosine kinase, a prominent axon guidance molecule, has recently been implicated in the regulation of neuroinflammation. Using a mouse model of brain injury and GFP bone marrow (BM) chimeric approach, we find neuroprotection and lack of significant motor deficits that is marked by reduced monocyte/macrophage cortical infiltration, and increased number of arginase-1-postivity in the absence of BM-derived Epha4. This was accompanied by a shift in monocyte gene profile from pro-to anti-inflammatory that includes increased Tek (Tie2 receptor) expression. Inhibition of Tie2 attenuated enhanced expression of M2-like genes in cultured Epha4-null monocyte/macrophages. In Epha4 BMdeficient mice, cortical-isolated GFP+ monocyte/macrophages displayed a phenotypic shift from classical to an intermediate subtype, which displayed reduced Ly6c hi concomitant with increased Ly6c lo -and Tie2-expressing populations. Furthermore, clodronate liposome-mediated monocyte depletion mimicked these effects in wild-type but resulted in attenuation of phenotype in Epha4 BM-deficient mice suggesting control over monocyte polarization not recruitment dictates tissue damage. Thus, coordination of monocyte pro-inflammatory polarization by Epha4 is a key regulatory step mediating neural tissue damage.

Brain injury resulting from repeated mild traumatic insult is associated with cognitive dysfunction and other chronic co-morbidities. The current study tested the effects of aberrant neurogenesis in a mouse model of repeated mild traumatic brain injury (rmTBI). Using Barnes Maze analysis, we found a significant reduction in spatial learning and memory at 24 days post-rmTBI compared to repeated sham (rSham) injury. Cell fate analysis showed a greater number of BrdU-labeled cells which co-expressed Prox-1 in the DG of rmTBI-injured mice which coincided with enhanced cFos expression for neuronal activity. We then selectively ablated dividing neural progenitor cells using a 7-day continuous infusion of Ara-C prior to rSham or rmTBI. This resulted in attenuation of cFos and BrdU-labeled cell changes and prevented associated learning and memory deficits. We further showed this phenotype was ameliorated in EphA4f./f/Tie2-Cre knockout compared to EphA4f./f wild type mice, which coincided with altered mRNA transcript levels of MCP-1, Cx43 and TGFβ. These findings demonstrate that cognitive decline is associated with an increased presence of immature neurons and gene expression changes in the DG following rmTBI. Our data also suggests that vascular EphA4-mediated neurogenic remodeling adversely affects learning and memory behavior in response to repeated insult.