Inhibitory neuronal changes following a mixed diffuse‐focal model of traumatic brain injury

Abstract

Traumatic brain injury (TBI) can result in excitation: inhibition imbalance, as well as a range of chronic neurological deficits. However, how TBI affects different interneurons, and how this relates to behavioral abnormalities, remains poorly understood. This study examined the effects of a mixed diffuse‐focal model of TBI, the lateral fluid percussion injury (LFPI), on interneurons, 8 weeks post‐TBI in rats. Brains were labeled with antibodies against calbindin, parvalbumin, calretinin, neuropeptide Y, and somatostatin, and the number of interneurons were assessed in the cortex and hippocampus following LFPI. LFPI caused a reduction in the numbers of interneurons mediating both perisomatic and dendritic inhibition in the somatosensory cortex. In hippocampus, there were heterogenous changes in the number of interneurons while motor cortex, showed no obvious loss in any of the subsets of interneurons after TBI. In parallel to the investigations of changes in the number of interneurons, we also investigated the long‐term behavioral consequences of LFPI. Behaviorally, rats given an LFPI displayed transient reduction in performance in motor tasks and were significantly impaired in reversal learning in the water maze task post‐TBI. We also report here progressive neurodegeneration in cortex and hippocampus indicated by Fluoro‐Jade C in the different brain areas examined after injury. Our findings suggest differential vulnerability of inhibitory neurons to LFPI in the different brain areas examined after injury. These data will aid in evaluation of new treatments for TBI and help target specific neuronal subtypes as a function of injury time and type.

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.…”

Hippocampal-Dependent Cognitive Dysfunction following Repeated Diffuse Rotational Brain Injury in Male and Female Mice

“…Main effect of injury, CHIMERA < Sham Main effect of sex, Male < Female TFC-cue test, total freezing during trace periods (Fig. 9D) COGNITIVE DYSFUNCTION FOLLOWING CHIMERA focal concussive 39,58 or lateral fluid percussion injury, [59][60][61][62] which results in a mixed focal-diffuse injury. In addition, CCI resulted in a reduction in PV-expressing interneurons in both the HP and AMY.…”

Metformin Reduces Repeat Mild Concussive Injury Pathophysiology

“…It has been suggested that inhibitory neurons, particularly parvalbumin-positive fast-spiking interneurons, are vulnerable to all magnitudes of TBI ( Hsieh et al, 2017 ; Tucker et al, 2019 ; Broussard et al, 2020 ; Cantu et al, 2020 ; Carron et al, 2020 ). rmCHI has been demonstrated to result in the loss of hippocampal parvalbumin-positive interneurons ( Tucker et al, 2019 ), while metformin treatment can enhance cell survival signaling in some experimental models ( Ge et al, 2017 ; Tang et al, 2017 ).…”

“…It has been suggested that inhibitory neurons, particularly parvalbumin-positive fast-spiking interneurons, are vulnerable to all magnitudes of TBI (Hsieh et al, 2017;Tucker et al, 2019;Broussard et al, 2020;Cantu et al, 2020;Carron et al, 2020). Repeat mCHI has been demonstrated…”