Astrocytic dysfunction in epileptogenesis

TY - JOUR

T1 - Astrocytic dysfunction in epileptogenesis

T2 - consequence of altered potassium and glutamate homeostasis?

AU - David, Yaron

AU - Cacheaux, Luisa P

AU - Ivens, Sebastian

AU - Lapilover, Ezequiel

AU - Heinemann, Uwe

AU - Kaufer, Daniela

AU - Friedman, Alon

PY - 2009/8/26

Y1 - 2009/8/26

N2 - 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 (>100 Hz) decreased facilitation of EPSPs, while potassium accumulation leads to frequency-dependent (10-50 Hz) and NMDA-dependent 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 frequency-dependent neuronal hyperexcitability and network synchronization.

AB - 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 (>100 Hz) decreased facilitation of EPSPs, while potassium accumulation leads to frequency-dependent (10-50 Hz) and NMDA-dependent 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 frequency-dependent neuronal hyperexcitability and network synchronization.

KW - Albumins

KW - Animals

KW - Astrocytes

KW - Computer Simulation

KW - Deoxycholic Acid

KW - Disease Models, Animal

KW - Epilepsy

KW - Excitatory Amino Acid Agonists

KW - Excitatory Postsynaptic Potentials

KW - Gene Expression Regulation

KW - Glial Fibrillary Acidic Protein

KW - Glutamic Acid

KW - In Vitro Techniques

KW - Male

KW - Models, Neurological

KW - Neocortex

KW - Oligonucleotide Array Sequence Analysis

KW - Patch-Clamp Techniques

KW - Potassium

KW - Rats

KW - Rats, Wistar

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

KW - Research Support, U.S. Gov't, Non-P.H.S.

U2 - 10.1523/JNEUROSCI.2323-09.2009

DO - 10.1523/JNEUROSCI.2323-09.2009

M3 - SCORING: Journal article

C2 - 19710312

VL - 29

SP - 10588

EP - 10599

JO - J NEUROSCI

JF - J NEUROSCI

SN - 0270-6474

IS - 34

ER -