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Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition
Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure...
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Published in: | Experimental neurology 2017-02, Vol.288, p.122-133 |
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description | Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c-Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1–5days postinfusion) and late (16–43days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1–2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4–5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamu\s, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process.
•Inhibition of glutamine synthetase in the hippocampal formation leads to epilepsy.•The epileptic seizures involve a small number of brain areas initially.•The seizures are mostly low grade (not severe) during the early phase.•The seizures progressively worsen over the next several weeks.•The worsening is accompanied by seizure involvement of multiple brain areas. |
doi_str_mv | 10.1016/j.expneurol.2016.10.007 |
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•Inhibition of glutamine synthetase in the hippocampal formation leads to epilepsy.•The epileptic seizures involve a small number of brain areas initially.•The seizures are mostly low grade (not severe) during the early phase.•The seizures progressively worsen over the next several weeks.•The worsening is accompanied by seizure involvement of multiple brain areas.</description><identifier>ISSN: 0014-4886</identifier><identifier>EISSN: 1090-2430</identifier><identifier>DOI: 10.1016/j.expneurol.2016.10.007</identifier><identifier>PMID: 27769717</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; c-Fos ; Disease Models, Animal ; Electroencephalography ; Entorhinal cortex ; Enzyme Inhibitors - toxicity ; Epilepsy - chemically induced ; Epileptogenesis ; Glutamate-Ammonia Ligase - metabolism ; Hippocampus ; Hippocampus - cytology ; Hippocampus - drug effects ; Hippocampus - physiology ; Limbic structures ; Male ; Methionine Sulfoximine - toxicity ; Muscarinic Agonists - toxicity ; Neurons - drug effects ; Neurons - pathology ; Pilocarpine - toxicity ; Rats ; Rats, Sprague-Dawley</subject><ispartof>Experimental neurology, 2017-02, Vol.288, p.122-133</ispartof><rights>2016 Elsevier Inc.</rights><rights>Copyright © 2016 Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c475t-5f53f5e7b78a3e217ee62c9eff961c28e400fceee72e5110fc4a592852241d753</citedby><cites>FETCH-LOGICAL-c475t-5f53f5e7b78a3e217ee62c9eff961c28e400fceee72e5110fc4a592852241d753</cites><orcidid>0000-0001-9217-6393 ; 0000-0001-5296-9575</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27769717$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Albright, Benjamin</creatorcontrib><creatorcontrib>Dhaher, Roni</creatorcontrib><creatorcontrib>Wang, Helen</creatorcontrib><creatorcontrib>Harb, Roa</creatorcontrib><creatorcontrib>Lee, Tih-Shih W.</creatorcontrib><creatorcontrib>Zaveri, Hitten</creatorcontrib><creatorcontrib>Eid, Tore</creatorcontrib><title>Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition</title><title>Experimental neurology</title><addtitle>Exp Neurol</addtitle><description>Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c-Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1–5days postinfusion) and late (16–43days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1–2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4–5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamu\s, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process.
•Inhibition of glutamine synthetase in the hippocampal formation leads to epilepsy.•The epileptic seizures involve a small number of brain areas initially.•The seizures are mostly low grade (not severe) during the early phase.•The seizures progressively worsen over the next several weeks.•The worsening is accompanied by seizure involvement of multiple brain areas.</description><subject>Animals</subject><subject>c-Fos</subject><subject>Disease Models, Animal</subject><subject>Electroencephalography</subject><subject>Entorhinal cortex</subject><subject>Enzyme Inhibitors - toxicity</subject><subject>Epilepsy - chemically induced</subject><subject>Epileptogenesis</subject><subject>Glutamate-Ammonia Ligase - metabolism</subject><subject>Hippocampus</subject><subject>Hippocampus - cytology</subject><subject>Hippocampus - drug effects</subject><subject>Hippocampus - physiology</subject><subject>Limbic structures</subject><subject>Male</subject><subject>Methionine Sulfoximine - toxicity</subject><subject>Muscarinic Agonists - toxicity</subject><subject>Neurons - drug effects</subject><subject>Neurons - pathology</subject><subject>Pilocarpine - toxicity</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><issn>0014-4886</issn><issn>1090-2430</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><recordid>eNqFkU2P0zAQhi0EYrsLfwF85JJiO3GcXJBWKz5WWgkOcLZcZ9JO5dhZ26nov8elSwUnLvZo5p13RvMQ8pazNWe8fb9fw8_ZwxKDW4uSKNk1Y-oZWXHWs0o0NXtOVozxpmq6rr0i1yntGWN9I9RLciWUanvF1Yo8fothGyElPAD9beiNo8ZmPJiMwZfQhmk2HiFRmNHBnMMWPCRM1JolwUA3R7rDeQ7WFKGjW7dkM6EHmo4-7yCbBBT9Djd4cnxFXozGJXj99N-QH58-fr_7Uj18_Xx_d_tQ2UbJXMlR1qMEtVGdqUFwBdAK28M49i23ooOGsdECgBIgOS9xY2QvOilEwwcl6xvy4ew7L5sJBgs-R-P0HHEy8aiDQf1vxeNOb8NBS1kWaFkxePdkEMPjAinrCZMF54yHsCTNu1pKUZ6-SNVZamNIKcJ4GcOZPgHTe30Bpk_AToUCrHS--XvLS98fQkVwexZAudUBIepkEbyFASPYrIeA_x3yCx-jsVg</recordid><startdate>20170201</startdate><enddate>20170201</enddate><creator>Albright, Benjamin</creator><creator>Dhaher, Roni</creator><creator>Wang, Helen</creator><creator>Harb, Roa</creator><creator>Lee, Tih-Shih W.</creator><creator>Zaveri, Hitten</creator><creator>Eid, Tore</creator><general>Elsevier Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9217-6393</orcidid><orcidid>https://orcid.org/0000-0001-5296-9575</orcidid></search><sort><creationdate>20170201</creationdate><title>Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition</title><author>Albright, Benjamin ; Dhaher, Roni ; Wang, Helen ; Harb, Roa ; Lee, Tih-Shih W. ; Zaveri, Hitten ; Eid, Tore</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c475t-5f53f5e7b78a3e217ee62c9eff961c28e400fceee72e5110fc4a592852241d753</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>c-Fos</topic><topic>Disease Models, Animal</topic><topic>Electroencephalography</topic><topic>Entorhinal cortex</topic><topic>Enzyme Inhibitors - toxicity</topic><topic>Epilepsy - chemically induced</topic><topic>Epileptogenesis</topic><topic>Glutamate-Ammonia Ligase - metabolism</topic><topic>Hippocampus</topic><topic>Hippocampus - cytology</topic><topic>Hippocampus - drug effects</topic><topic>Hippocampus - physiology</topic><topic>Limbic structures</topic><topic>Male</topic><topic>Methionine Sulfoximine - toxicity</topic><topic>Muscarinic Agonists - toxicity</topic><topic>Neurons - drug effects</topic><topic>Neurons - pathology</topic><topic>Pilocarpine - toxicity</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Albright, Benjamin</creatorcontrib><creatorcontrib>Dhaher, Roni</creatorcontrib><creatorcontrib>Wang, Helen</creatorcontrib><creatorcontrib>Harb, Roa</creatorcontrib><creatorcontrib>Lee, Tih-Shih W.</creatorcontrib><creatorcontrib>Zaveri, Hitten</creatorcontrib><creatorcontrib>Eid, Tore</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Experimental neurology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Albright, Benjamin</au><au>Dhaher, Roni</au><au>Wang, Helen</au><au>Harb, Roa</au><au>Lee, Tih-Shih W.</au><au>Zaveri, Hitten</au><au>Eid, Tore</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition</atitle><jtitle>Experimental neurology</jtitle><addtitle>Exp Neurol</addtitle><date>2017-02-01</date><risdate>2017</risdate><volume>288</volume><spage>122</spage><epage>133</epage><pages>122-133</pages><issn>0014-4886</issn><eissn>1090-2430</eissn><abstract>Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c-Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1–5days postinfusion) and late (16–43days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1–2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4–5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamu\s, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process.
•Inhibition of glutamine synthetase in the hippocampal formation leads to epilepsy.•The epileptic seizures involve a small number of brain areas initially.•The seizures are mostly low grade (not severe) during the early phase.•The seizures progressively worsen over the next several weeks.•The worsening is accompanied by seizure involvement of multiple brain areas.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27769717</pmid><doi>10.1016/j.expneurol.2016.10.007</doi><tpages>12</tpages><orcidid>https://orcid.org/0000-0001-9217-6393</orcidid><orcidid>https://orcid.org/0000-0001-5296-9575</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals c-Fos Disease Models, Animal Electroencephalography Entorhinal cortex Enzyme Inhibitors - toxicity Epilepsy - chemically induced Epileptogenesis Glutamate-Ammonia Ligase - metabolism Hippocampus Hippocampus - cytology Hippocampus - drug effects Hippocampus - physiology Limbic structures Male Methionine Sulfoximine - toxicity Muscarinic Agonists - toxicity Neurons - drug effects Neurons - pathology Pilocarpine - toxicity Rats Rats, Sprague-Dawley |
title | Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition |
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