Traumatic Brain Injury Increases Cortical Glutamate Network Activity by Compromising GABAergic Control

Cantú, David; Walker, Kendall R.; Lau, Lauren A.; Taylor-Weiner, Amaro; Hampton, David W.; Tesco, Giuseppina; Dulla, Chris G.

doi:10.1093/cercor/bhu041

Cited by 172 publications

(170 citation statements)

References 76 publications

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“…Given the significant neuropathological changes following rmTBI, it is surprising to find no accompanying electrophysiological changes. The lack of synaptic excitability changes observed after rmTBI in this study contrast with recent findings after severe TBI from our lab in juvenile rats (Nichols et al 2015) and from previous reports in adult animals (Cantu et al 2014). As this study only examined animals at 14 days after injury it will be important to examine changes that may occur in the acute and more chronic time points after rmTBI.…”

Section: Discussioncontrasting

confidence: 84%

Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Goddeyne

Nichols

et al. 2015

Journal of Neurophysiology

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Goddeyne C, Nichols J, Wu C, Anderson T. Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats. J Neurophysiol 113: 3268 -3280, 2015. First published February 18, 2015 doi:10.1152/jn.00970.2014.-Traumatic brain injury (TBI) most frequently occurs in pediatric patients and remains a leading cause of childhood death and disability. Mild TBI (mTBI) accounts for nearly 75% of all TBI cases, yet its neuropathophysiology is still poorly understood. While even a single mTBI injury can lead to persistent deficits, repeat injuries increase the severity and duration of both acute symptoms and long-term deficits. In this study, to model pediatric repetitive mTBI (rmTBI) we subjected unrestrained juvenile animals (postnatal day 20) to repeat weight-drop impacts. Animals were anesthetized and subjected to sham injury or rmTBI once per day for 5 days. Magnetic resonance imaging (MRI) performed 14 days after injury revealed marked cortical atrophy and ventriculomegaly in rmTBI animals. Specifically, beneath the impact zone the thickness of the cortex was reduced by up to 46% and the area of the ventricles increased by up to 970%. Immunostaining with the neuron-specific marker NeuN revealed an overall loss of neurons within the motor cortex but no change in neuronal density. Examination of intrinsic and synaptic properties of layer II/III pyramidal neurons revealed no significant difference between sham-injured and rmTBI animals at rest or under convulsant challenge with the potassium channel blocker 4-aminopyridine. Overall, our findings indicate that the neuropathological changes reported after pediatric rmTBI can be effectively modeled by repeat weight drop in juvenile animals. Developing a better understanding of how rmTBI alters the pediatric brain may help improve patient care and direct "return to game" decision making in adolescents.concussion; electrophysiology; MRI; pediatrics; traumatic brain injury

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Section: Discussioncontrasting

confidence: 84%

Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Goddeyne

Nichols

et al. 2015

Journal of Neurophysiology

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“…The latter phenomenon is also suggested to occur not via structural changes but through an imbalance in excitation-inhibition (Merzenich et al, 1984; Benali et al, 2008; Mix et al, 2010; Ding et al, 2011). Since there is good evidence for the existence of this after trauma, as indicated by reductions in GABA receptors and increased glutamate signaling (Lee et al, 2011; Raible et al, 2012; Cantu et al, 2014; Drexel et al, 2015), as well as structural alterations in the perineuronal nets on GABAergic neurons (Celio et al, 1998; Harris et al, 2009a), then changes in receptive field size and ensuing unmasking of existing or construction of new synapses, or simply changes in synaptic strength and efficacy might well underpin alterations in the observed functional connectivity. Although there is much to learn about the biology that underlies connectivity changes, it is tempting to consider whether these early network changes reflect a period of brain reorganization and whether rehabilitative “behavioral shaping” interventions would be optimally applied during or before this time to guide construction of new or repair of existing circuits.…”

Section: Discussionmentioning

confidence: 99%

Disconnection and hyper-connectivity underlie reorganization after TBI: A rodent functional connectomic analysis

Harris

Verley

Gutman

et al. 2016

Experimental Neurology

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While past neuroimaging methods have contributed greatly to our understanding of brain function after traumatic brain injury (TBI), resting state functional MRI (rsfMRI) connectivity methods have more recently provided a far more unbiased approach with which to monitor brain circuitry compared to task-based approaches. However, current knowledge on the physiologic underpinnings of the correlated blood oxygen level dependent signal, and how changes in functional connectivity relate to reorganizational processes that occur following injury is limited. The degree and extent of this relationship remain to be determined in order that rsfMRI methods can be fully adapted for determining the optimal timing and type of rehabilitative interventions that can be used post-TBI to achieve the best outcome. Very few rsfMRI studies exist after experimental TBI and therefore we chose to acquire rsfMRI data before and at 7, 14 and 28 days after experimental TBI using a well-known, clinically-relevant, unilateral controlled cortical impact injury (CCI) adult rat model of TBI. This model was chosen since it has widespread axonal injury, a well-defined time-course of reorganization including spine, dendrite, axonal and cortical map changes, as well as spontaneous recovery of sensorimotor function by 28 d post-injury from which to interpret alterations in functional connectivity. Data were co-registered to a parcellated rat template to generate adjacency matrices for network analysis by graph theory. Making no assumptions about direction of change, we used two-tailed statistical analysis over multiple brain regions in a data-driven approach to access global and regional changes in network topology in order to assess brain connectivity in an unbiased way. Our main hypothesis was that deficits in functional connectivity would become apparent in regions known to be structurally altered or deficient in axonal connectivity in this model. The data show the loss of functional connectivity predicted by the structural deficits, not only within the primary sensorimotor injury site and pericontused regions, but the normally connected homotopic cortex, as well as subcortical regions, all of which persisted chronically. Especially novel in this study is the unanticipated finding of widespread increases in connection strength that dwarf both the degree and extent of the functional disconnections, and which persist chronically in some sensorimotor and subcortically connected regions. Exploratory global network analysis showed changes in network parameters indicative of possible acutely increased random connectivity and temporary reductions in modularity that were matched by local increases in connectedness and increased efficiency among more weakly connected regions. The global network parameters: shortest path-length, clustering coefficient and modularity that were most affected by trauma also scaled with the severity of injury, so that the corresponding regional measures were correlated to the injury severity most notably at 7 and 14 days and esp...

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“…An early and persistent increase in hippocampal excitability has been observed in both patients and animal models [24]. This net increase in excitability is thought to result from the selective loss of vulnerable inhibitory interneurons concurrent with the reorganization of excitatory circuitry [25, 26]. Recurrent excitatory circuitry in the hippocampal dentate gyrus may manifest as mossy fiber sprouting, where the axons of dentate granule cells form abnormal connections with neighboring neurons in response to a loss of CA3 pyramidal cell targets and hilar interneurons [27, 28].…”

Section: Traumatic Brain Injury and Epilepsymentioning

confidence: 99%

Inflammation in epileptogenesis after traumatic brain injury

Webster

Sun

Crack

et al. 2017

J Neuroinflammation

232

185

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BackgroundEpilepsy is a common and debilitating consequence of traumatic brain injury (TBI). Seizures contribute to progressive neurodegeneration and poor functional and psychosocial outcomes for TBI survivors, and epilepsy after TBI is often resistant to existing anti-epileptic drugs. The development of post-traumatic epilepsy (PTE) occurs in a complex neurobiological environment characterized by ongoing TBI-induced secondary injury processes. Neuroinflammation is an important secondary injury process, though how it contributes to epileptogenesis, and the development of chronic, spontaneous seizure activity, remains poorly understood. A mechanistic understanding of how inflammation contributes to the development of epilepsy (epileptogenesis) after TBI is important to facilitate the identification of novel therapeutic strategies to reduce or prevent seizures.BodyWe reviewed previous clinical and pre-clinical data to evaluate the hypothesis that inflammation contributes to seizures and epilepsy after TBI. Increasing evidence indicates that neuroinflammation is a common consequence of epileptic seizure activity, and also contributes to epileptogenesis as well as seizure initiation (ictogenesis) and perpetuation. Three key signaling factors implicated in both seizure activity and TBI-induced secondary pathogenesis are highlighted in this review: high-mobility group box protein-1 interacting with toll-like receptors, interleukin-1β interacting with its receptors, and transforming growth factor-β signaling from extravascular albumin. Lastly, we consider age-dependent differences in seizure susceptibility and neuroinflammation as mechanisms which may contribute to a heightened vulnerability to epileptogenesis in young brain-injured patients.ConclusionSeveral inflammatory mediators exhibit epileptogenic and ictogenic properties, acting on glia and neurons both directly and indirectly influence neuronal excitability. Further research is required to establish causality between inflammatory signaling cascades and the development of epilepsy post-TBI, and to evaluate the therapeutic potential of pharmaceuticals targeting inflammatory pathways to prevent or mitigate the development of PTE.

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Traumatic Brain Injury Increases Cortical Glutamate Network Activity by Compromising GABAergic Control

Cited by 172 publications

References 76 publications

Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Repetitive mild traumatic brain injury induces ventriculomegaly and cortical thinning in juvenile rats

Disconnection and hyper-connectivity underlie reorganization after TBI: A rodent functional connectomic analysis

Inflammation in epileptogenesis after traumatic brain injury

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