Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio
Abstract Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traum...
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creator | MacMullin, Paul Hodgson, Nathaniel Damar, Ugur Lee, Henry Hing Cheong Hameed, Mustafa Q Dhamne, Sameer C Hyde, Damon Conley, Grace M Morriss, Nicholas Qiu, Jianhua Mannix, Rebekah Hensch, Takao K Rotenberg, Alexander |
description | Abstract
Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traumatic phases. We therefore measured seizure threshold and cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) concentrations, 1 and 6 weeks after rmTBI in mice. We also analyzed the structure of parvalbumin-positive interneurons (PVIs), their perineuronal nets (PNNs), and their electroencephalography (EEG) signature (gamma frequency band power). For mechanistic insight, we measured cortical oxidative stress, reflected in the reduced/oxidized glutathione (GSH/GSSG) ratio. We found that seizure susceptibility increased both early and late after rmTBI. However, whereas increased Glu dominated the E/I 1 week after rmTBI, Glu concentration normalized and the E/I was instead characterized by depressed GABA, reduced per-PVI parvalbumin expression, and reduced gamma EEG power at the 6-week post-rmTBI time point. Oxidative stress was increased early after rmTBI, where transient PNN degradation was noted, and progressed throughout the monitoring period. We conclude that GSH depletion, perhaps triggered by early Glu-mediated excitotoxicity, leads to late post-rmTBI loss of PVI-dependent cortical inhibitory tone. We thus propose dampening of Glu signaling, maintenance of redox state, and preservation of PVI inhibitory capacity as therapeutic targets for post-rmTBI treatment. |
doi_str_mv | 10.1093/cercor/bhaa157 |
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Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traumatic phases. We therefore measured seizure threshold and cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) concentrations, 1 and 6 weeks after rmTBI in mice. We also analyzed the structure of parvalbumin-positive interneurons (PVIs), their perineuronal nets (PNNs), and their electroencephalography (EEG) signature (gamma frequency band power). For mechanistic insight, we measured cortical oxidative stress, reflected in the reduced/oxidized glutathione (GSH/GSSG) ratio. We found that seizure susceptibility increased both early and late after rmTBI. However, whereas increased Glu dominated the E/I 1 week after rmTBI, Glu concentration normalized and the E/I was instead characterized by depressed GABA, reduced per-PVI parvalbumin expression, and reduced gamma EEG power at the 6-week post-rmTBI time point. Oxidative stress was increased early after rmTBI, where transient PNN degradation was noted, and progressed throughout the monitoring period. We conclude that GSH depletion, perhaps triggered by early Glu-mediated excitotoxicity, leads to late post-rmTBI loss of PVI-dependent cortical inhibitory tone. We thus propose dampening of Glu signaling, maintenance of redox state, and preservation of PVI inhibitory capacity as therapeutic targets for post-rmTBI treatment.</description><identifier>ISSN: 1047-3211</identifier><identifier>EISSN: 1460-2199</identifier><identifier>DOI: 10.1093/cercor/bhaa157</identifier><identifier>PMID: 32676666</identifier><language>eng</language><publisher>United States: Oxford University Press</publisher><subject>Animals ; Brain - metabolism ; Brain - physiopathology ; Brain Concussion - complications ; Gamma Rhythm ; gamma-Aminobutyric Acid - metabolism ; Glutamic Acid - metabolism ; Interneurons - physiology ; Male ; Mice, Inbred C57BL ; Original ; Oxidative Stress ; Parvalbumins - analysis ; Seizures - etiology ; Seizures - metabolism ; Seizures - physiopathology</subject><ispartof>Cerebral cortex (New York, N.Y. 1991), 2020-11, Vol.30 (12), p.6108-6120</ispartof><rights>The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com 2020</rights><rights>The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-b050ddceac08aef5a76efe7345de3197b6ef0b5130abde6a9216f9c5c5c6000d3</citedby><cites>FETCH-LOGICAL-c424t-b050ddceac08aef5a76efe7345de3197b6ef0b5130abde6a9216f9c5c5c6000d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32676666$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>MacMullin, Paul</creatorcontrib><creatorcontrib>Hodgson, Nathaniel</creatorcontrib><creatorcontrib>Damar, Ugur</creatorcontrib><creatorcontrib>Lee, Henry Hing Cheong</creatorcontrib><creatorcontrib>Hameed, Mustafa Q</creatorcontrib><creatorcontrib>Dhamne, Sameer C</creatorcontrib><creatorcontrib>Hyde, Damon</creatorcontrib><creatorcontrib>Conley, Grace M</creatorcontrib><creatorcontrib>Morriss, Nicholas</creatorcontrib><creatorcontrib>Qiu, Jianhua</creatorcontrib><creatorcontrib>Mannix, Rebekah</creatorcontrib><creatorcontrib>Hensch, Takao K</creatorcontrib><creatorcontrib>Rotenberg, Alexander</creatorcontrib><title>Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio</title><title>Cerebral cortex (New York, N.Y. 1991)</title><addtitle>Cereb Cortex</addtitle><description>Abstract
Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traumatic phases. We therefore measured seizure threshold and cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) concentrations, 1 and 6 weeks after rmTBI in mice. We also analyzed the structure of parvalbumin-positive interneurons (PVIs), their perineuronal nets (PNNs), and their electroencephalography (EEG) signature (gamma frequency band power). For mechanistic insight, we measured cortical oxidative stress, reflected in the reduced/oxidized glutathione (GSH/GSSG) ratio. We found that seizure susceptibility increased both early and late after rmTBI. However, whereas increased Glu dominated the E/I 1 week after rmTBI, Glu concentration normalized and the E/I was instead characterized by depressed GABA, reduced per-PVI parvalbumin expression, and reduced gamma EEG power at the 6-week post-rmTBI time point. Oxidative stress was increased early after rmTBI, where transient PNN degradation was noted, and progressed throughout the monitoring period. We conclude that GSH depletion, perhaps triggered by early Glu-mediated excitotoxicity, leads to late post-rmTBI loss of PVI-dependent cortical inhibitory tone. We thus propose dampening of Glu signaling, maintenance of redox state, and preservation of PVI inhibitory capacity as therapeutic targets for post-rmTBI treatment.</description><subject>Animals</subject><subject>Brain - metabolism</subject><subject>Brain - physiopathology</subject><subject>Brain Concussion - complications</subject><subject>Gamma Rhythm</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Glutamic Acid - metabolism</subject><subject>Interneurons - physiology</subject><subject>Male</subject><subject>Mice, Inbred C57BL</subject><subject>Original</subject><subject>Oxidative Stress</subject><subject>Parvalbumins - analysis</subject><subject>Seizures - etiology</subject><subject>Seizures - metabolism</subject><subject>Seizures - physiopathology</subject><issn>1047-3211</issn><issn>1460-2199</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUtvEzEUhUcIREthyxJ5CRLT2J73BikNECJVatXA2rrjuUOMZuzBj4jwz_h3OExawQp74de537nySZKXjF4y2mQLiVYau2h3AKyoHiXnLC9pylnTPI57mldpxhk7S545941SVvGCP03OMl5WZRznya-NlhbBIVGabFH9DBbJNjiJk1etGpQ_kGXv0ZI7nNArr_ZIVkbL4JwyOt66MHhHemtGcvNDdfBHsfUWnXtLbsHuYWjDqHR6a9xcvtGRpzHYWP_-4PqgpT-yQHfkSk07cEqS-77csbH1EDyM4HGxXl4tyV00Mc-TJz0MDl-c1ovky8cPn1ef0uub9Wa1vE5lznOftrSgXScRJK0B-wKqEnussrzoMGNN1cYjbQuWUWg7LKHhrOwbWcRZUkq77CJ5N3On0I4YSdpbGMRk1Qj2IAwo8e-LVjvx1exFzfO6zmgEvD4BrPke0Hkxqvi_wwAaTXCC57yITnXNovRylkprnLPYP9gwKo55izlvcco7Frz6u7kH-X3AUfBmFpgw_Q_2G-COvk0</recordid><startdate>20201103</startdate><enddate>20201103</enddate><creator>MacMullin, Paul</creator><creator>Hodgson, Nathaniel</creator><creator>Damar, Ugur</creator><creator>Lee, Henry Hing Cheong</creator><creator>Hameed, Mustafa Q</creator><creator>Dhamne, Sameer C</creator><creator>Hyde, Damon</creator><creator>Conley, Grace M</creator><creator>Morriss, Nicholas</creator><creator>Qiu, Jianhua</creator><creator>Mannix, Rebekah</creator><creator>Hensch, Takao K</creator><creator>Rotenberg, Alexander</creator><general>Oxford University Press</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></search><sort><creationdate>20201103</creationdate><title>Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio</title><author>MacMullin, Paul ; Hodgson, Nathaniel ; Damar, Ugur ; Lee, Henry Hing Cheong ; Hameed, Mustafa Q ; Dhamne, Sameer C ; Hyde, Damon ; Conley, Grace M ; Morriss, Nicholas ; Qiu, Jianhua ; Mannix, Rebekah ; Hensch, Takao K ; Rotenberg, Alexander</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-b050ddceac08aef5a76efe7345de3197b6ef0b5130abde6a9216f9c5c5c6000d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Brain - metabolism</topic><topic>Brain - physiopathology</topic><topic>Brain Concussion - complications</topic><topic>Gamma Rhythm</topic><topic>gamma-Aminobutyric Acid - metabolism</topic><topic>Glutamic Acid - metabolism</topic><topic>Interneurons - physiology</topic><topic>Male</topic><topic>Mice, Inbred C57BL</topic><topic>Original</topic><topic>Oxidative Stress</topic><topic>Parvalbumins - analysis</topic><topic>Seizures - etiology</topic><topic>Seizures - metabolism</topic><topic>Seizures - physiopathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>MacMullin, Paul</creatorcontrib><creatorcontrib>Hodgson, Nathaniel</creatorcontrib><creatorcontrib>Damar, Ugur</creatorcontrib><creatorcontrib>Lee, Henry Hing Cheong</creatorcontrib><creatorcontrib>Hameed, Mustafa Q</creatorcontrib><creatorcontrib>Dhamne, Sameer C</creatorcontrib><creatorcontrib>Hyde, Damon</creatorcontrib><creatorcontrib>Conley, Grace M</creatorcontrib><creatorcontrib>Morriss, Nicholas</creatorcontrib><creatorcontrib>Qiu, Jianhua</creatorcontrib><creatorcontrib>Mannix, Rebekah</creatorcontrib><creatorcontrib>Hensch, Takao K</creatorcontrib><creatorcontrib>Rotenberg, Alexander</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>Cerebral cortex (New York, N.Y. 1991)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>MacMullin, Paul</au><au>Hodgson, Nathaniel</au><au>Damar, Ugur</au><au>Lee, Henry Hing Cheong</au><au>Hameed, Mustafa Q</au><au>Dhamne, Sameer C</au><au>Hyde, Damon</au><au>Conley, Grace M</au><au>Morriss, Nicholas</au><au>Qiu, Jianhua</au><au>Mannix, Rebekah</au><au>Hensch, Takao K</au><au>Rotenberg, Alexander</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio</atitle><jtitle>Cerebral cortex (New York, N.Y. 1991)</jtitle><addtitle>Cereb Cortex</addtitle><date>2020-11-03</date><risdate>2020</risdate><volume>30</volume><issue>12</issue><spage>6108</spage><epage>6120</epage><pages>6108-6120</pages><issn>1047-3211</issn><eissn>1460-2199</eissn><abstract>Abstract
Chronic symptoms indicating excess cortical excitability follow mild traumatic brain injury, particularly repetitive mild traumatic brain injury (rmTBI). Yet mechanisms underlying post-traumatic excitation/inhibition (E/I) ratio abnormalities may differ between the early and late post-traumatic phases. We therefore measured seizure threshold and cortical gamma-aminobutyric acid (GABA) and glutamate (Glu) concentrations, 1 and 6 weeks after rmTBI in mice. We also analyzed the structure of parvalbumin-positive interneurons (PVIs), their perineuronal nets (PNNs), and their electroencephalography (EEG) signature (gamma frequency band power). For mechanistic insight, we measured cortical oxidative stress, reflected in the reduced/oxidized glutathione (GSH/GSSG) ratio. We found that seizure susceptibility increased both early and late after rmTBI. However, whereas increased Glu dominated the E/I 1 week after rmTBI, Glu concentration normalized and the E/I was instead characterized by depressed GABA, reduced per-PVI parvalbumin expression, and reduced gamma EEG power at the 6-week post-rmTBI time point. Oxidative stress was increased early after rmTBI, where transient PNN degradation was noted, and progressed throughout the monitoring period. We conclude that GSH depletion, perhaps triggered by early Glu-mediated excitotoxicity, leads to late post-rmTBI loss of PVI-dependent cortical inhibitory tone. We thus propose dampening of Glu signaling, maintenance of redox state, and preservation of PVI inhibitory capacity as therapeutic targets for post-rmTBI treatment.</abstract><cop>United States</cop><pub>Oxford University Press</pub><pmid>32676666</pmid><doi>10.1093/cercor/bhaa157</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Animals Brain - metabolism Brain - physiopathology Brain Concussion - complications Gamma Rhythm gamma-Aminobutyric Acid - metabolism Glutamic Acid - metabolism Interneurons - physiology Male Mice, Inbred C57BL Original Oxidative Stress Parvalbumins - analysis Seizures - etiology Seizures - metabolism Seizures - physiopathology |
title | Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio |
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