Chronic Posttraumatic Epilepsy following Neocortical Undercut Lesion in Mice

Ping, Xingjie; Jin, Xiaoming

doi:10.1371/journal.pone.0158231

Cited by 25 publications

(14 citation statements)

References 44 publications

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“…We analyzed FS interneurons of neocortical layer V in the UC model to determine whether there were abnormalities in their axons and presynaptic terminals that could result in defects in GABAergic transmission. Interictal discharges originate in layer V of the UC (Prince and Tseng, 1993); (Hoffman et al, 1994) and alterations in FS interneurons in this lamina could contribute to hyperexcitability and epileptiform bursts in in vitro cortical slices (Prince and Tseng, 1993; Hoffman et al, 1994) and seizures in vivo (Chauvette et al, 2016; Ping and Jin, 2016a). We identified FS cells in whole cell recordings from their electrophysiological phenotype (Xiang et al, 1998) and, retrospectively, appearance following biocytin labeling.…”

Section: Methodsmentioning

confidence: 99%

Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis

Parada

Shen

et al. 2017

Neurobiology of Disease

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Electrophysiological experiments in the partial cortical isolation (“undercut” or “UC”) model of injury-induced neocortical epileptogenesis have shown alterations in GABAergic synaptic transmission attributable to abnormalities in presynaptic terminals. To determine whether the decreased inhibition was associated with structural abnormalities in GABAergic interneurons, we used immunocytochemical techniques, confocal microscopy and EM in UC and control sensorimotor rat cortex to analyze structural alterations in fast-spiking parvalbumin-containing interneurons and pyramidal (Pyr) cells of layer V. Principle findings were: 1) There were no decreases in counts of parvalbumin (PV)- or GABA-immunoreactive interneurons in UC cortex, however there were significant reductions in expression of VGAT and GAD-65 and -67 in halos of GABAergic terminals around Pyr somata in layer V. 2) Consistent with previous results, somatic size and density of Pyr cells was decreased in infragranular layers of UC cortex. 3) Dendrites of biocytin-filled FS interneurons were significantly decreased in volume. 4) There were decreases in the size and VGAT content of GABAergic boutons in axons of biocytin-filled FS cells in the UC, together with a decrease in colocalization with postsynaptic gephyrin, suggesting a reduction in GABAergic synapses. Quantitative EM of layer V Pyr somata confirmed the reduction in inhibitory synapses. 5) There were marked and lasting reductions in brain derived neurotrophic factor (BDNF)-IR and -mRNA in Pyr cells and decreased TrkB-IR on PV cells in UC cortex. 6) Results lead to the hypothesis that reduction in trophic support by BDNF derived from Pyr cells may contribute to the regressive changes in axonal terminals and dendrites of FS cells in the UC cortex and decreased GABAergic inhibition.

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Section: Methodsmentioning

confidence: 99%

Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis

Parada

Shen

et al. 2017

Neurobiology of Disease

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“…This protection in the zero maze was unaffected by either CB 1 or CB 2 receptor antagonists, suggesting that these receptors are dispensable. Modeling post-traumatic epilepsy is time consuming and faces other challenges such as a low percentage of animals that develop epilepsy ( Mazarati, 2006 ), however, recent models that produce consistent replication of spontaneous seizure activity following a TBI are available ( Ping and Jin, 2016 ). Contrary to preclinical research demonstrating that the eCB system plays a protective roles against seizures ( Wallace et al, 2001 ; Marsicano et al, 2003 ), a CB 1 receptor antagonist has protected against injury-induced seizure threshold deficits as well as lowered seizure mortality ( Wang et al, 2016 ), potentially through the disinhibition of GABAergic terminals.…”

Section: Pre-clinical Evaluation Of Cannabinoids To Treat Tbimentioning

confidence: 99%

Endocannabinoids: A Promising Impact for Traumatic Brain Injury

Schurman

Lichtman

2017

Front. Pharmacol.

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The endogenous cannabinoid (endocannabinoid) system regulates a diverse array of physiological processes and unsurprisingly possesses considerable potential targets for the potential treatment of numerous disease states, including two receptors (i.e., CB1 and CB2 receptors) and enzymes regulating their endogenous ligands N-arachidonoylethanolamine (anandamide) and 2-arachidonyl glycerol (2-AG). Increases in brain levels of endocannabinoids to pathogenic events suggest this system plays a role in compensatory repair mechanisms. Traumatic brain injury (TBI) pathology remains mostly refractory to currently available drugs, perhaps due to its heterogeneous nature in etiology, clinical presentation, and severity. Here, we review pre-clinical studies assessing the therapeutic potential of cannabinoids and manipulations of the endocannabinoid system to ameliorate TBI pathology. Specifically, manipulations of endocannabinoid degradative enzymes (e.g., fatty acid amide hydrolase, monoacylglycerol lipase, and α/β-hydrolase domain-6), CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating cellular and molecular hallmarks of TBI pathology such as; cell death, excitotoxicity, neuroinflammation, cerebrovascular breakdown, and cell structure and remodeling. TBI-induced behavioral deficits, such as learning and memory, neurological motor impairments, post-traumatic convulsions or seizures, and anxiety also respond to manipulations of the endocannabinoid system. As such, the endocannabinoid system possesses potential drugable receptor and enzyme targets for the treatment of diverse TBI pathology. Yet, full characterization of TBI-induced changes in endocannabinoid ligands, enzymes, and receptor populations will be important to understand that role this system plays in TBI pathology. Promising classes of compounds, such as the plant-derived phytocannabinoids, synthetic cannabinoids, and endocannabinoids, as well as their non-cannabinoid receptor targets, such as TRPV1 receptors, represent important areas of basic research and potential therapeutic interest to treat TBI.

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“…Spontaneous behavioral seizures occur in animals with partial neocortical isolations ( Graber and Prince 2006 ; Chauvette et al. 2016 ; Ping and Jin 2016 ), and UC slices are hyperexcitable and generate spontaneous and evoked epileptiform bursts ( Hoffman et al. 1994 ; Graber and Prince 1999 ; Li et al.…”

Section: Resultsmentioning

confidence: 99%

Partial Activation of TrkB Receptors Corrects Interneuronal Calcium Channel Dysfunction and Reduces Epileptogenic Activity in Neocortex following Injury

Parada

Yang

et al. 2020

Cerebral Cortex

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Decreased GABAergic inhibition due to dysfunction of inhibitory interneurons plays an important role in post-traumatic epileptogenesis. Reduced N-current Ca2+ channel function in GABAergic terminals contributes to interneuronal abnormalities and neural circuit hyperexcitability in the partial neocortical isolation (undercut, UC) model of post-traumatic epileptogenesis. Because brain-derived neurotrophic factor (BDNF) supports the development and maintenance of interneurons, we hypothesized that the activation of BDNF tropomyosin kinase B (TrkB) receptors by a small molecule, TrkB partial agonist, PTX BD4-3 (BD), would correct N channel abnormalities and enhance inhibitory synaptic transmission in UC cortex. Immunocytochemistry (ICC) and western blots were used to quantify N- and P/Q-type channels. We recorded evoked (e)IPSCs and responses to N and P/Q channel blockers to determine the effects of BD on channel function. Field potential recordings were used to determine the effects of BD on circuit hyperexcitability. Chronic BD treatment 1) upregulated N and P/Q channel immunoreactivity in GABAergic terminals; 2) increased the effects of N or P/Q channel blockade on evoked inhibitory postsynaptic currents (eIPSCs); 3) increased GABA release probability and the frequency of sIPSCs; and 4) reduced the incidence of epileptiform discharges in UC cortex. The results suggest that chronic TrkB activation is a promising approach for rescuing injury-induced calcium channel abnormalities in inhibitory terminals, thereby improving interneuronal function and suppressing circuit hyperexcitability.

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Chronic Posttraumatic Epilepsy following Neocortical Undercut Lesion in Mice

Cited by 25 publications

References 44 publications

Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis

Structural alterations in fast-spiking GABAergic interneurons in a model of posttraumatic neocortical epileptogenesis

Endocannabinoids: A Promising Impact for Traumatic Brain Injury

Partial Activation of TrkB Receptors Corrects Interneuronal Calcium Channel Dysfunction and Reduces Epileptogenic Activity in Neocortex following Injury

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