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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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 |
format | Article |
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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.</description><identifier>ISSN: 1078-8956</identifier><identifier>EISSN: 1546-170X</identifier><identifier>DOI: 10.1038/nm.2850</identifier><identifier>PMID: 22797810</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject><![CDATA[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]]></subject><ispartof>Nature medicine, 2012-08, Vol.18 (8), p.1271-1278</ispartof><rights>Springer Nature America, Inc. 2012</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Aug 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c645t-84d7be350d64efdc839a06b036f1f0065d9f4e02618160884d2709a8bb9e427f3</citedby><cites>FETCH-LOGICAL-c645t-84d7be350d64efdc839a06b036f1f0065d9f4e02618160884d2709a8bb9e427f3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nm.2850$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nm.2850$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22797810$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Koyama, Ryuta</creatorcontrib><creatorcontrib>Tao, Kentaro</creatorcontrib><creatorcontrib>Sasaki, Takuya</creatorcontrib><creatorcontrib>Ichikawa, Junya</creatorcontrib><creatorcontrib>Miyamoto, Daisuke</creatorcontrib><creatorcontrib>Muramatsu, Rieko</creatorcontrib><creatorcontrib>Matsuki, Norio</creatorcontrib><creatorcontrib>Ikegaya, Yuji</creatorcontrib><title>GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy</title><title>Nature medicine</title><addtitle>Nat Med</addtitle><addtitle>Nat Med</addtitle><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.</description><subject>631/80/86</subject><subject>692/699/375</subject><subject>692/700/565</subject><subject>Animals</subject><subject>Animals, Suckling</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain Diseases - etiology</subject><subject>Brain Diseases - physiopathology</subject><subject>Brain Diseases - prevention & control</subject><subject>Bumetanide - pharmacology</subject><subject>Bumetanide - therapeutic use</subject><subject>Cancer Research</subject><subject>Care and treatment</subject><subject>Cell adhesion & migration</subject><subject>Cell Lineage</subject><subject>Cell Movement</subject><subject>Choristoma - etiology</subject><subject>Choristoma - physiopathology</subject><subject>Choristoma - prevention & control</subject><subject>Complications and side 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excitation after febrile seizures induces ectopic granule cells and adult epilepsy</title><author>Koyama, Ryuta ; Tao, Kentaro ; Sasaki, Takuya ; Ichikawa, Junya ; Miyamoto, Daisuke ; Muramatsu, Rieko ; Matsuki, Norio ; Ikegaya, Yuji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c645t-84d7be350d64efdc839a06b036f1f0065d9f4e02618160884d2709a8bb9e427f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>631/80/86</topic><topic>692/699/375</topic><topic>692/700/565</topic><topic>Animals</topic><topic>Animals, Suckling</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain Diseases - etiology</topic><topic>Brain Diseases - physiopathology</topic><topic>Brain Diseases - prevention & control</topic><topic>Bumetanide - pharmacology</topic><topic>Bumetanide - therapeutic use</topic><topic>Cancer Research</topic><topic>Care and treatment</topic><topic>Cell adhesion & migration</topic><topic>Cell Lineage</topic><topic>Cell Movement</topic><topic>Choristoma - etiology</topic><topic>Choristoma - physiopathology</topic><topic>Choristoma - prevention & control</topic><topic>Complications and side effects</topic><topic>Convulsions & seizures</topic><topic>Dentate Gyrus</topic><topic>Diagnosis</topic><topic>Disease Susceptibility</topic><topic>Epilepsy</topic><topic>Epilepsy, Temporal Lobe - etiology</topic><topic>Epilepsy, Temporal Lobe - physiopathology</topic><topic>Epilepsy, Temporal Lobe - prevention & control</topic><topic>Febrile convulsions</topic><topic>GABA</topic><topic>GABA Agonists - therapeutic use</topic><topic>GABA Antagonists - toxicity</topic><topic>gamma-Aminobutyric Acid - physiology</topic><topic>Genes, Reporter</topic><topic>Granulation tissue</topic><topic>Health aspects</topic><topic>Hippocampus - pathology</topic><topic>Hippocampus - physiopathology</topic><topic>Hyperthermia, Induced - 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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.</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> |
fulltext | fulltext |
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ispartof | Nature medicine, 2012-08, Vol.18 (8), p.1271-1278 |
issn | 1078-8956 1546-170X |
language | eng |
recordid | cdi_proquest_miscellaneous_1419362744 |
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 |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-21T05%3A21%3A51IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=GABAergic%20excitation%20after%20febrile%20seizures%20induces%20ectopic%20granule%20cells%20and%20adult%20epilepsy&rft.jtitle=Nature%20medicine&rft.au=Koyama,%20Ryuta&rft.date=2012-08-01&rft.volume=18&rft.issue=8&rft.spage=1271&rft.epage=1278&rft.pages=1271-1278&rft.issn=1078-8956&rft.eissn=1546-170X&rft_id=info:doi/10.1038/nm.2850&rft_dat=%3Cgale_proqu%3EA300182928%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1040232620&rft_id=info:pmid/22797810&rft_galeid=A300182928&rfr_iscdi=true |