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-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.

Hippocampal Interneuronal Dysfunction and Hyperexcitability in a Porcine Model of Concussion

“…Hippocampal CA1 hyperexcitability and epileptogenesis caused by changes in the sodium channel expressed in inhibitory PV + interneurons have been previously reported (Liautard, Scalmani et al 2013). While histological and electrophysiological studies have previously identified PV + interneurons to be selectively altered in experimental models of rodent TBI (Nichols, Bjorklund et al 2018, Carron, Sun et al 2020, Figueiredo, Harbert et al 2020, MacMullin, Hodgson et al 2020), we could not identify a specific sodium channel responsible for the observed changes in CA1 interneurons following concussion. Using NEURON model of a CA1 PV + interneuron (specifically basket cell), we observed a reduction in the sodium channel window current which in turn may also affect resurgent and/or persistent currents generated by voltage-gated sodium channels (for review, see (Eijkelkamp, Linley et al 2012)).…”

“…Hippocampal CA1 hyperexcitability and epileptogenesis caused by changes in the sodium channel expressed in inhibitory PV + interneurons have been previously reported (Liautard, Scalmani et al 2013). While histological and electrophysiological studies have previously identified PV + interneurons to be selectively altered in experimental models of rodent TBI (Nichols, Bjorklund et al 2018, Carron, Sun et al 2020, Figueiredo, Harbert et al 2020, MacMullin, Hodgson et al 2020, we could not identify a specific sodium channel responsible for the observed changes in CA1 interneurons following concussion.…”

Factors influencing the acute pentylenetetrazole‐induced seizure paradigm and a literature review

“…Cohorts of wild‐type control mice were included in this analysis, some of which have previously been published. 29 , 30 Wild‐type mice on both pure C57BL/6J and mixed (129S4/SvJae, C57BL/6J, and CBA) backgrounds were used. 31 Ages of mice were grouped as follows, in accordance with widely accepted guidelines: pup (P0 to P21), juvenile (3–6 weeks), young adult (6–12 weeks), mature adult (13 weeks to 6 months), middle‐aged adult (10–14 months), and old‐aged adult (over 18 months).…”

Structural changes in the neocortex as correlates of variations in EEG spectra and seizure susceptibility in rat brains with different degrees of dysplasia

“…This may reflect two aspects of the influence of these neurons on cortical activity. On the one hand, their main function is to support the regularity of discharges within the gamma frequency range (Sohal et al., 2009 ), with inhibitory effects on irregular and abnormal overexcitation; on the other hand, they provide supportive preservation of neuronal activities in states of energy deficiency during and after seizures (MacMullin et al., 2020 ). In this article, however, the expected more specific and stronger correlation with changes in gamma band power has not been distinguished, so in this case, the influence of PV+ neurons might be much broader.…”