Increase in Seizure Susceptibility After Repetitive Concussion Results from Oxidative Stress, Parvalbumin-Positive Interneuron Dysfunction and Biphasic Increases in Glutamate/GABA Ratio.

Autor:	MacMullin P; F.M. Kirby Neurobiology Center, Department of Neurology., Hodgson N; F.M. Kirby Neurobiology Center, Department of Neurology., Damar U; F.M. Kirby Neurobiology Center, Department of Neurology., Lee HHC; F.M. Kirby Neurobiology Center, Department of Neurology., Hameed MQ; F.M. Kirby Neurobiology Center, Department of Neurology.; Department of Neurosurgery., Dhamne SC; F.M. Kirby Neurobiology Center, Department of Neurology., Hyde D; F.M. Kirby Neurobiology Center, Department of Neurology., Conley GM; Department of Emergency Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Morriss N; Department of Emergency Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Qiu J; Department of Emergency Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Mannix R; Department of Emergency Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Hensch TK; F.M. Kirby Neurobiology Center, Department of Neurology., Rotenberg A; F.M. Kirby Neurobiology Center, Department of Neurology.
Jazyk:	angličtina
Zdroj:	Cerebral cortex (New York, N.Y. : 1991) [Cereb Cortex] 2020 Nov 03; Vol. 30 (12), pp. 6108-6120.
DOI:	10.1093/cercor/bhaa157
Abstrakt:	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. (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)
Databáze:	MEDLINE
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