Microglia dynamics in adolescent traumatic brain injury

Abstract

Repetitive, mild traumatic brain injuries (RmTBIs) are increasingly common in adolescents and encompass one of the largest neurological health concerns in the world. Adolescence is a critical period for brain development where RmTBIs can substantially impact neurodevelopmental trajectories and life-long neurological health. Our current understanding of RmTBI pathophysiology suggests key roles for neuroinflammation in negatively regulating neural health and function. Microglia, the brain's resident immune population, play important roles in brain development by regulating neuronal number, and synapse formation and elimination. In response to injury, microglia activate to inflammatory phenotypes that may detract from these normal homeostatic, physiological, and developmental roles. To date, however, little is known regarding the impact of RmTBIs on microglia function during adolescent brain development. This review details key concepts surrounding RmTBI pathophysiology, adolescent brain development, and microglia dynamics in the developing brain and in response to injury, in an effort to formulate a hypothesis on how the intersection of these processes may modify long-term trajectories.

Keywords: Brain maturation; Complement cascade; Glia; Pathophysiology; Synaptic pruning; White matter.

Fig. 1

Primary and secondary injury cascades following TBI. a Diffuse axonal injury that results from the differential velocities of white and grey matter during a traumatic impact induces tensile strain and microtubule damage within axons. This event induces accumulation of microtubule transport proteins/cargo and calcium influx, resulting in axonal swelling and ultimately axonal degeneration. b TBI reduces cerebral blood flow through impaired autoregulation and increased vasoconstriction, thereby reducing glucose and oxygen throughout the brain. c Axonal stretching induces mechanoporation, facilitating depolarization via the influx of sodium and calcium ions. Additionally, reductions in oxygen and glucose delivery reduce neuronal ATP levels causing failure or reversal of ATP-dependent ion transporters/pumps such as the sodium/potassium ATP pump. This further exacerbates ionic dysregulation by exporting potassium and importing sodium ions. d Ionic imbalances which lead to depolarization of pre-synaptic neurons result in dysregulated glutamate release into the synaptic cleft, which over-activates NMDAR receptors and increases calcium influx into post-synaptic neurons (termed excitotoxicity). e Unregulated calcium influx drives neuronal death through mitochondrial dysfunction and the release of reactive oxygen species (ROS)

Fig. 2

Microglia phenotypes following TBI. DAMPs released by injured, damaged, and/or degrading brain cells activate microglia from homeostatic surveillance/ramified phenotypes to activated inflammatory/amoeboid phenotypes. Activated microglia may differentiate along a spectrum of pro-inflammatory (M1-like) and anti-inflammatory (M2-like) phenotypes, synthesizing and releasing a plethora of pro- and anti-inflammatory cytokines/chemokines, respectively

Fig. 3

Complement-mediated synaptic pruning by microglia in the homeostatic and RmTBI adolescent brain. a Under homeostatic conditions, the complement protein C3 is converted to C3b by C3 convertase which tags unnecessary or weak synapses for pruning. Microglia, which highly express the C3 receptor (C3R), bind to synaptically tagged C3 molecules facilitating microglia-mediated pruning of pre-synaptic terminals. b Following RmTBI, microglia-mediated synaptic pruning may be either increased or decreased compared to homeostatic conditions. Ramified microglia are thought to be more efficient at synaptic pruning compared to amoeboid microglia, which could reduce pruning during adolescence. Alternatively, increased expression of C3 following RmTBI may facilitate increased synaptic pruning by activated/amoeboid microglia. Collectively, alterations in synaptic pruning caused by RmTBIs may directly influence synaptic density and overarching neural development and health

Fig. 4

Trends in microglia activation and neurological impairments following adolescent RmTBI. Throughout life, microglia are known to become increasingly activated. In addition, neurological impairments increase throughout adulthood and ageing. RmTBIs sustained in adolescence may cause earlier chronic or primed microglia activation that may persist into adulthood and through aging. Increased microglia activation during the adolescent developmental period may therefore influence the acquisition or onset of neurological impairments throughout life. Disruption to neurological functioning may induce negative consequences through adulthood into aging