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

Ryuta Koyama; Kentaro Tao; Takuya Sasaki; Junya Ichikawa; Daisuke Miyamoto; Rieko Muramatsu; Norio Matsuki; Yuji Ikegaya

doi:10.1038/nm.2850

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

Ryuta Koyama^*, Kentaro Tao, Takuya Sasaki, Junya Ichikawa, Daisuke Miyamoto, Rieko Muramatsu, Norio Matsuki, Yuji Ikegaya

^*Corresponding author for this work

Research Center for Idling Brain Science, Organization for Promotion of Research

Research output: Contribution to journal › Article › peer-review

156 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	1271-1278
Number of pages	8
Journal	Nature Medicine
Volume	18
Issue number	8
DOIs	https://doi.org/10.1038/nm.2850
State	Published - 2012/08

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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title = "GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy",

abstract = "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 GABAA receptors (GABAA-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABAA-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 GABAA-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.",

author = "Ryuta Koyama and Kentaro Tao and Takuya Sasaki and Junya Ichikawa and Daisuke Miyamoto and Rieko Muramatsu and Norio Matsuki and Yuji Ikegaya",

note = "Funding Information: This work was supported by a Grant-in-Aid for Science Research on Young Scientists (B) (19790048) and on Innovative Areas {\textquoteleft}Mesoscopic Neurocircuitry{\textquoteright} (22115003) from The Ministry of Education, Culture, Sports, Science and Technology of Japan; the Research Foundation for Pharmaceutical Sciences; and the Funding Program for Next Generation World-Leading Researchers (LS023).",

year = "2012",

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doi = "10.1038/nm.2850",

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volume = "18",

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T1 - GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy

AU - Koyama, Ryuta

AU - Tao, Kentaro

AU - Sasaki, Takuya

AU - Ichikawa, Junya

AU - Miyamoto, Daisuke

AU - Muramatsu, Rieko

AU - Matsuki, Norio

AU - Ikegaya, Yuji

N1 - Funding Information: This work was supported by a Grant-in-Aid for Science Research on Young Scientists (B) (19790048) and on Innovative Areas ‘Mesoscopic Neurocircuitry’ (22115003) from The Ministry of Education, Culture, Sports, Science and Technology of Japan; the Research Foundation for Pharmaceutical Sciences; and the Funding Program for Next Generation World-Leading Researchers (LS023).

PY - 2012/8

Y1 - 2012/8

N2 - 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 GABAA receptors (GABAA-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABAA-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 GABAA-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.

AB - 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 GABAA receptors (GABAA-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABAA-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 GABAA-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.

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

Abstract

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