GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy.
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.
Laboratory of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan. rkoyama@mol.f.u-tokyo.ac.jp
Ryuta
R
Koyama
Kentaro
K
Tao
Takuya
T
Sasaki
Junya
J
Ichikawa
Daisuke
D
Miyamoto
Rieko
R
Muramatsu
Norio
N
Matsuki
Yuji
Y
Ikegaya
D000818:Animals; D000833:Animals, Suckling; D001927:Brain Diseases / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D002034:Bumetanide / Q000494:pharmacology / Q000627:therapeutic use; D019070:Cell Lineage; D002465:Cell Movement; D002828:Choristoma / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control; D018891:Dentate Gyrus; D004198:Disease Susceptibility; D004833:Epilepsy, Temporal Lobe / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D018755:GABA Agonists / Q000627:therapeutic use; D018756:GABA Antagonists / Q000633:toxicity; D017930:Genes, Reporter; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D006979:Hyperthermia, Induced / Q000009:adverse effects; D008297:Male; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009928:Organ Specificity; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D003294:Seizures, Febrile / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics / Q000502:physiology; D064506:Solute Carrier Family 12, Member 2; D015854:Up-Regulation; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D018755:GABA Agonists; D018756:GABA Antagonists; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; C578879:Slc12a2 protein, rat; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D002034:Bumetanide; D005680:gamma-Aminobutyric Acid