Role of Astrocytes in Post-traumatic Epilepsy

Abstract

Traumatic brain injury, a common cause of acquired epilepsy, is typical to find necrotic cell death within the injury core. The dynamic changes in astrocytes surrounding the injury core contribute to epileptic seizures associated with intense neuronal firing. However, little is known about the molecular mechanisms that activate astrocytes during traumatic brain injury or the effect of functional changes of astrocytes on seizures. In this comprehensive review, we present our cumulated understanding of the complex neurological affection in astrocytes after traumatic brain injury. We approached the problem through describing the changes of cell morphology, neurotransmitters, biochemistry, and cytokines in astrocytes during post-traumatic epilepsy. In addition, we also discussed the relationship between dynamic changes in astrocytes and seizures and the current pharmacologic agents used for treatment. Hopefully, this review will provide a more detailed knowledge from which better therapeutic strategies can be developed to treat post-traumatic epilepsy.

Keywords: astrocytes; epilepsy; hyperexcitability; neuron; traumatic brain injury.

Figure 1

The interaction between astrocytes and epilepsy induced by traumatic brain injury. A contemporary view of how traumatic brain injury induces post-traumatic epilepsy. Orange dots represent sites where astrocytes may be involved in the regulation of post-traumatic epilepsy. NMDA, N-methyl-D-aspartate; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, γ-aminobutyric acid.

Figure 2

Representative molecular mechanism of post-traumatic epilepsy involved in astrocytes. The exposure of brain tissue to extravasated serum albumin induces activation of TGF-β/ALK5 signaling in astrocytes. IL-1β and TNFα implicated in NMDA and AMPA receptor activation inducing Ca²⁺ influx in a dose-dependent manner. In addition, IL-1β and TNFα down-regulate the expression of Kir channels and weaken its clearance of extracellular K⁺. Decreased expression of Kir channels in concert with dislocation of AQP4 channels in astrocytes contribute to impaired K⁺ buffering. In this context, reactive astrocytes dramatically transform in their morphology and function. Reactive astrocyte is characterized by the proliferation of astrocytes and the hallmark accumulation of GFAP. Traumatic brain injury also causes a deranged glutamate uptake and a decreased GABA release. The high-mobility group box-1 is an additional inflammatory agent produced by reactive astrocytes and mediated by the toll-like receptor 4. Finally, the expression of Cx43 protein is different in human and animal. It is generally shown to be increased in human, whereas findings from animal models are conflicting. Arrows show the flow direction. The red forks represent the disordered functions. Some mechanisms are indicated by abbreviations. GFAP, glial fibrillary acidic protein; NMDA, N-methyl-D-aspartate; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA, γ-aminobutyric acid; AQP4, aquaporin-4; TGF-β, transforming growth factor-β; Cx43, connexin-43; IL-1β, interleukin-1beta.