Astrocyte-mediated mechanisms contribute to traumatic brain injury pathology

Abstract

Astrocytes respond to traumatic brain injury (TBI) with changes to their molecular make-up and cell biology, which results in changes in astrocyte function. These changes can be adaptive, initiating repair processes in the brain, or detrimental, causing secondary damage including neuronal death or abnormal neuronal activity. The response of astrocytes to TBI is often-but not always-accompanied by the upregulation of intermediate filaments, including glial fibrillary acidic protein (GFAP) and vimentin. Because GFAP is often upregulated in the context of nervous system disturbance, reactive astrogliosis is sometimes treated as an "all-or-none" process. However, the extent of astrocytes' cellular, molecular, and physiological adjustments is not equal for each TBI type or even for each astrocyte within the same injured brain. Additionally, new research highlights that different neurological injuries and diseases result in entirely distinctive and sometimes divergent astrocyte changes. Thus, extrapolating findings on astrocyte biology from one pathological context to another is problematic. We summarize the current knowledge about astrocyte responses specific to TBI and point out open questions that the field should tackle to better understand how astrocytes shape TBI outcomes. We address the astrocyte response to focal versus diffuse TBI and heterogeneity of reactive astrocytes within the same brain, the role of intermediate filament upregulation, functional changes to astrocyte function including potassium and glutamate homeostasis, blood-brain barrier maintenance and repair, metabolism, and reactive oxygen species detoxification, sex differences, and factors influencing astrocyte proliferation after TBI. This article is categorized under: Neurological Diseases > Molecular and Cellular Physiology.

Keywords: TBI; astrocyte; gliosis; heterogeneity; traumatic brain injury.

Figure 1.

Differences in astrocyte response depending on the type of injury. A) Schematic of the astrocyte response to focal injury. Astrocytes form a glial border around the lesion site, characterized by the upregulation of GFAP. Astrocytes closest to the lesion adopt a palisading phenotype and are more likely to proliferate. An overall decrease in Glt1 has been detected in focal injury TBI, but where the astrocytes with decreased Glt1 are located relative to the injury is not clear. B) Schematic of the astrocyte response to diffuse injury. In diffuse injury, no glial border is formed. At least two subtypes of astrocytes response can be found: astrocytes that upregulate GFAP, and astrocytes with an atypical response, in which there is not GFAP upregulation and the expression of astrocytes key proteins and markers decrease. Created with Biorender.

Figure 2.

On the left, a simplified summary of the metabolic coupling between astrocytes and neurons. On the right, a representation of anomalies in astrocyte-neuron metabolic coupling after TBI. In red, the pathways/proteins that are changed after TBI. TCA: tricarboxylic acid cycle, PPP: pentose phosphate pathway, Gln: glutamine, Glu:glutamate, AcCoA: acetylCoA. Created with Biorender.