A potential role for glia‐derived extracellular matrix remodeling in postinjury epilepsy

Abstract

Head trauma and vascular injuries are known risk factors for acquired epilepsy. The sequence of events that lead from the initial injury to the development of epilepsy involves complex plastic changes and circuit rewiring. In-depth, comprehensive understanding of the epileptogenic process is critical for the identification of disease-modifying targets. Here we review the complex interactions of cellular and extracellular components that may promote epileptogenesis, with an emphasis on the role of astrocytes. Emerging evidence demonstrates that astrocytes promptly respond to brain damage and play a critical role in the development of postinjury epilepsy. Astrocytes have been shown to regulate extracellular matrix (ECM) remodeling, which can affect plasticity and stability of synapses and, in turn, contribute to the epileptogenic process. From these separate lines of evidence, we present a hypothesis suggesting a possible role for astrocyte-regulated remodeling of ECM and perineuronal nets, a specialized ECM structure around fast-spiking inhibitory interneurons, in the development and progression of posttraumatic epilepsies. © 2016 Wiley Periodicals, Inc.

Dual roles of astrocytes in plasticity and reconstruction after traumatic brain injury

“…Epileptogenesis can be induced by several pathological processes, including glial scar, ECM remodeling, axonal plasticity alteration, excitation/inhibition imbalance, cell death, and neuronal heterotopia [167]. Once the structural integrity of PNNs is compromised by astrocyte-derived ECM molecules, dysfunctional PNNs around the fastspiking inhibitory interneurons might underlie excitation/inhibition imbalance and lead to the development of post-traumatic epilepsies [168]. The involvement of hyperphysiologic TNF-α in post-traumatic epileptogenesis has also been revealed [169,170].…”

Neuroinflammatory targets and treatments for epilepsy validated in experimental models

“…Exposure of the brain environment to either albumin or TGFβ1 was sufficient to induce both epileptiform activity and delayed spontaneous seizures. It is notable that blocking TGF signaling prevented most albumin‐induced hallmarks of epileptogenesis including TGF signaling, transcriptome‐wide changes, synaptogenesis, neurogenesis, PNN degradation, hyperexcitability, and seizures . Ongoing research evaluates the efficacy of multiple small molecules (acting as TGFb signaling inhibitors) in blocking or reversing the effects of BBB disruption on neuropathology, excitability, epilepsy development, and cognitive functions.…”

Astrocytes and Glutamine Synthetase in Epileptogenesis

“…However, immunohistochemical staining of hippocampal tissue excised from patients with mesial temporal lobe epilepsy have shown variable results with respect to EAAT1 and EAAT2 expression (Bjornsen et al, ; Eid et al, ; Mathern et al, ; Proper et al, ). Factors such as ischemia‐induced tissue proteolysis (Li, Zhou, & Danbolt, ), the area of the hippocampus being sampled (Bjornsen et al, ), and whether neuron loss and reactive gliosis (sclerosis) is present (Kim et al, ) possibly underlie this variability in the results.…”

“…The astrocytic pathologies to be discussed involve: (1) alterations in astrocyte transport—that is, aquaporin 4 and the associated α‐syntrophin‐dystrophin complex; the inwardly rectifying potassium channel Kir4.1; the excitatory amino acid transporters EAAT1 and EAAT2; and the monocarboxylate transporters MCT1 and MCT2, and (2) perturbations in glutamine synthetase (GS) . Other astrocyte‐related pathologies may also play important roles in epileptogenesis, and the reader is referred to several excellent papers on topics such as adenosine and adenosine kinase (Boison, ), gap junctions and hemichannels (Bedner et al, ), inflammation (Vezzani, ; Vezzani, Aronica, Mazarati, & Pittman, ; Zhang, Zou, Han, Rensing, & Wong, ), monoamines (Svob Strac et al, ), extracellular matrix components (Dzwonek & Wilczynski, ; Kim, Porter, Friedman, & Kaufer, ), and the blood‐brain barrier (Friedman, Kaufer, & Heinemann, ).…”