Astrocyte dysfunction in temporal lobe epilepsy: K⁺ channels and gap junction coupling

Abstract

Astrocytes are endowed with the machinery to sense and respond to neuronal activity. Recent work has demonstrated that astrocytes play important physiological roles in the CNS, e.g., they synchronize action potential firing, ensure ion homeostasis, transmitter clearance and glucose metabolism, and regulate the vascular tone. Astrocytes are abundantly coupled through gap junctions, which is a prerequisite to redistribute elevated K 1 from sites of excessive neuronal activity to sites of lower extracellular K 1 concentration. Recent studies identified dysfunctional astrocytes as crucial players in epilepsy. Investigation of specimens from patients with pharmacoresistant temporal lobe epilepsy and epilepsy models revealed alterations in expression, localization, and function of astroglial inwardly rectifying K 1 (Kir) channels, particularly Kir4.1, which is suspected to entail impaired K 1 buffering. Gap junctions in astrocytes appear to play a dual role: on the one hand they counteract the generation of hyperactivity by facilitating clearance of elevated extracellular K 1 levels while in contrast, they constitute a pathway for energetic substrate delivery to fuel neuronal (hyper)activity. Recent work suggests that astrocyte dysfunction is causative of the generation or spread of seizure activity. Thus, astrocytes should be considered as promising targets for alternative antiepileptic therapies. V V C 2012 Wiley Periodicals, Inc.

High-Throughput LC–MS/MS Proteomic Analysis of a Mouse Model of Mesiotemporal Lobe Epilepsy Predicts Microglial Activation Underlying Disease Development

“…In brain tissue from epileptic patients, astrocytes undergo significant changes in their physiological properties, and are involved in the activation of inflammatory pathways 70 . In particular, reactive astrogliosis with modified astroglial function may play an important role in the generation and spread of seizure activity 71 . It has been suggested that proinflammatory molecules can change glio-neuronal communications and contribute to the generation of seizures and seizure-related neuronal damage 70 .…”

Expressional Analysis of Inwardly Rectifying Kir4.1 Channels in Groggy Rats, a Rat Model of Absence Seizures

“…All of the mutations in patients with EAST syndrome cause drastic decreases in K + buffering currents mediated by both Kir4.1 and Kir4.1/5.1 channels, implying that the impaired functioning of Kir4.1 disrupts spatial K + buffering and causes epileptic seizures (15)(16)(17). In addition, it has also been shown that expressional levels of Kir4.1 were altered in animal models of epilepsy (18,19), as well as in patients with temporal lobe epilepsy (20)(21)(22). All these findings strongly suggest that Kir4.1 channels are involved in the pathogenesis of GTC and/or temporal lobe seizures.…”

Differential TGF-β Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice

“…Indeed, recent findings from human epileptic tissue and animal models of epilepsy suggest a key role for astrocytic dysfunction in epileptogenesis, seizure generation, and seizure propagation (10,12,49,50). In particular, a significant role has been suggested for the downregulation of glial inward rectifying potassium (Kir) channel 4.1, which underlies impaired buffering of extracellular potassium (10,12,13). Because our previous molecular and physiological data in mouse and rat models of albumin-and TGF-b-induced seizures showed early activation of astrocytes (3,10), and specifically a robust excessive extracellular potassium accumulation upon repetitive stimulation at physiologically relevant frequencies (10-50 Hz) (10), we tested a potential role of such stimulation on neuronal excitability in the IL-6-treated cortices.…”