GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy

Febrile seizures during childhood are linked to the development of chronic epilepsy. Now, Ryuta Koyama and colleagues show that febrile seizures are associated with enhanced GABAergic excitation and ectopic granule cell migration in the hippocampus. Temporal lobe epilepsy (TLE) is accompanied by an...

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Veröffentlicht in:Nature medicine 2012-08, Vol.18 (8), p.1271-1278
Hauptverfasser: Koyama, Ryuta, Tao, Kentaro, Sasaki, Takuya, Ichikawa, Junya, Miyamoto, Daisuke, Muramatsu, Rieko, Matsuki, Norio, Ikegaya, Yuji
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container_end_page 1278
container_issue 8
container_start_page 1271
container_title Nature medicine
container_volume 18
creator Koyama, Ryuta
Tao, Kentaro
Sasaki, Takuya
Ichikawa, Junya
Miyamoto, Daisuke
Muramatsu, Rieko
Matsuki, Norio
Ikegaya, Yuji
description Febrile seizures during childhood are linked to the development of chronic epilepsy. Now, Ryuta Koyama and colleagues show that febrile seizures are associated with enhanced GABAergic excitation and ectopic granule cell migration in the hippocampus. Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA A receptors (GABA A -Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA A -Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na + K + 2Cl − co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA A -R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.
doi_str_mv 10.1038/nm.2850
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Now, Ryuta Koyama and colleagues show that febrile seizures are associated with enhanced GABAergic excitation and ectopic granule cell migration in the hippocampus. Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA A receptors (GABA A -Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA A -Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na + K + 2Cl − co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. 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Now, Ryuta Koyama and colleagues show that febrile seizures are associated with enhanced GABAergic excitation and ectopic granule cell migration in the hippocampus. Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA A receptors (GABA A -Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA A -Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na + K + 2Cl − co-transporter (NKCC1), which regulates the excitatory action of GABA. 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Now, Ryuta Koyama and colleagues show that febrile seizures are associated with enhanced GABAergic excitation and ectopic granule cell migration in the hippocampus. Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA A receptors (GABA A -Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA A -Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na + K + 2Cl − co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA A -R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>22797810</pmid><doi>10.1038/nm.2850</doi><tpages>8</tpages></addata></record>
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source MEDLINE; Springer Nature - Complete Springer Journals; Nature Journals Online
subjects 631/80/86
692/699/375
692/700/565
Animals
Animals, Suckling
Biomedical and Life Sciences
Biomedicine
Brain Diseases - etiology
Brain Diseases - physiopathology
Brain Diseases - prevention & control
Bumetanide - pharmacology
Bumetanide - therapeutic use
Cancer Research
Care and treatment
Cell adhesion & migration
Cell Lineage
Cell Movement
Choristoma - etiology
Choristoma - physiopathology
Choristoma - prevention & control
Complications and side effects
Convulsions & seizures
Dentate Gyrus
Diagnosis
Disease Susceptibility
Epilepsy
Epilepsy, Temporal Lobe - etiology
Epilepsy, Temporal Lobe - physiopathology
Epilepsy, Temporal Lobe - prevention & control
Febrile convulsions
GABA
GABA Agonists - therapeutic use
GABA Antagonists - toxicity
gamma-Aminobutyric Acid - physiology
Genes, Reporter
Granulation tissue
Health aspects
Hippocampus - pathology
Hippocampus - physiopathology
Hyperthermia, Induced - adverse effects
Infectious Diseases
Male
Metabolic Diseases
Molecular Medicine
Nerve Tissue Proteins - antagonists & inhibitors
Nerve Tissue Proteins - biosynthesis
Nerve Tissue Proteins - genetics
Nerve Tissue Proteins - physiology
Neurons
Neurons - metabolism
Neurons - pathology
Neurosciences
Organ Specificity
Pathogenesis
Physiological aspects
Rats
Rats, Sprague-Dawley
Receptors, GABA-A - biosynthesis
Receptors, GABA-A - genetics
Receptors, GABA-A - physiology
RNA Interference
Seizures, Febrile - complications
Seizures, Febrile - pathology
Seizures, Febrile - physiopathology
Signal transduction
Sodium-Potassium-Chloride Symporters - genetics
Sodium-Potassium-Chloride Symporters - physiology
Solute Carrier Family 12, Member 2
Up-Regulation
title GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy
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