Astrocytic dysfunction in epileptogenesis
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Astrocytic dysfunction in epileptogenesis : consequence of altered potassium and glutamate homeostasis? / David, Yaron; Cacheaux, Luisa P; Ivens, Sebastian; Lapilover, Ezequiel; Heinemann, Uwe; Kaufer, Daniela; Friedman, Alon.
In: J NEUROSCI, Vol. 29, No. 34, 26.08.2009, p. 10588-99.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -