Astrocytic Dysfunction in Epileptogenesis: Consequence of Altered Potassium and Glutamate Homeostasis?

Abstract

Focal epilepsy often develops following traumatic, ischemic, or infectious brain injury. While the electrical activity of the epileptic brain is well characterized, the mechanisms underlying epileptogenesis are poorly understood. We have recently shown that in the rat neocortex, long-lasting breakdown of the blood-brain barrier (BBB) or direct exposure of the neocortex to serum-derived albumin leads to rapid upregulation of the astrocytic marker GFAP (glial fibrillary acidic protein), followed by delayed (within 4 -7 d) development of an epileptic focus. We investigated the role of astrocytes in epileptogenesis in the BBB-breakdown and albumin models of epileptogenesis. We found similar, robust changes in astrocytic gene expression in the neocortex within hours following treatment with deoxycholic acid (BBB breakdown) or albumin. These changes predict reduced clearance capacity for both extracellular glutamate and potassium. Electrophysiological recordings in vitro confirmed the reduced clearance of activity-dependent accumulation of both potassium and glutamate 24 h following exposure to albumin. We used a NEURON model to simulate the consequences of reduced astrocytic uptake of potassium and glutamate on EPSPs. The model predicted that the accumulation of glutamate is associated with frequency-dependent (Ͼ100 Hz) decreased facilitation of EPSPs, while potassium accumulation leads to frequency-dependent (10 -50 Hz) and NMDAdependent synaptic facilitation. In vitro electrophysiological recordings during epileptogenesis confirmed frequency-dependent synaptic facilitation leading to seizure-like activity. Our data indicate a transcription-mediated astrocytic transformation early during epileptogenesis. We suggest that the resulting reduction in the clearance of extracellular potassium underlies frequencydependent neuronal hyperexcitability and network synchronization.

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

“…Increase in intrinsic excitability (47), selective excitatory synaptogenesis (48), and reduction in inhibitory transmission (14) were all reported to occur during epileptogenesis. Our recordings from neocortical pyramidal neurons indicate activity-dependent increase in excitability that does not require a prominent change in intrinsic properties and/or spontaneous synaptic transmission, and is probably astrocyte mediated (10). 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).…”

“…Our recordings from neocortical pyramidal neurons indicate activity-dependent increase in excitability that does not require a prominent change in intrinsic properties and/or spontaneous synaptic transmission, and is probably astrocyte mediated (10). 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).…”

“…We previously demonstrated TGF-b signaling and a robust inflammatory response in the brain of rats and FVB/N mice that were exposed to serum albumin (10,11,14,16). Furthermore, TGF-b1 pathway blockers efficiently blocked epileptogenesis in BBB breakdown and albumin models of epilepsy in mice and rats (11,16).…”

“…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.…”

“…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. Our recordings demonstrate a long-lasting depolarization (∼8 mV) upon afferent but not intracellular stimulation, predicting a 25% increase in the accumulation of extracellular potassium during neuronal activation, consistent with the notion of astrocytic dysfunction and reduced potassium buffering after insult (51,52) or during epileptogenesis (3,10).…”