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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Veröffentlicht in:Cerebral cortex (New York, N.Y. 1991) N.Y. 1991), 2020-11, Vol.30 (12), p.6108-6120
Hauptverfasser: 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
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container_end_page 6120
container_issue 12
container_start_page 6108
container_title Cerebral cortex (New York, N.Y. 1991)
container_volume 30
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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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. 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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 ; 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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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source Oxford University Press Journals All Titles (1996-Current); MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection
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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