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

• Published in: Nature medicine Vol. 18; no. 8; pp. 1271 - 1278
• Main Authors: Koyama, Ryuta, Tao, Kentaro, Sasaki, Takuya, Ichikawa, Junya, Miyamoto, Daisuke, Muramatsu, Rieko, Matsuki, Norio, Ikegaya, Yuji
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2012; Nature Publishing Group
• 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; Japan
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.2850

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.