<scp>TRPC</scp>3 channels play a critical role in the theta component of pilocarpine‐induced status epilepticus in mice

Phelan, Kevin D.; Shwe, U Thaung; Cozart, Michael; Wu, Hong; Mock, Matthew M; Abramowitz, Joel; Birnbaumer, Lutz; Zheng, Fang

doi:10.1111/epi.13648

Cited by 28 publications

(39 citation statements)

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“…2A,B) or pentylenetetrazol administration (Fig. 2C,D) failed as the neural activity after single administration of these chemical convulsants was far below the root mean square power of SE observed in unanesthetized mice 15 . However, we found that sequential administration of pilocarpine and pentylenetetrazol reliably induced seizures in anesthetized mice that were similar electrographically and behaviorally to the pilocarpine-induced seizures in unanesthetized mice (Fig.…”

Section: Resultsmentioning

confidence: 86%

“…pilocarpine-induced seizures and eeG recording. EEG head-mount surgery of age-matched (2.8 to 3-month-old) TRPC3smcKO and littermate control male mice was conducted as described previously 15 . Mice were administered a single dose of methylscopolamine nitrate (10 mg/kg, i.p.)…”

Section: Methodsmentioning

confidence: 99%

“…The canonical transient receptor potential 3 (TRPC3) channel has been increasingly implicated in SE [12][13][14] , and we recently reported that TRPC3 channels enhance seizure intensity 15 . TRPC3 channels are non-selective cation channels known primarily for their importance in regulating intracellular calcium.…”

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confidence: 99%

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Vascular smooth muscle TRPC3 channels facilitate the inverse hemodynamic response during status epilepticus

Cozart

Phelan

et al. 2020

Sci Rep

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Human status epilepticus (SE) is associated with a pathological reduction in cerebral blood flow termed the inverse hemodynamic response (IHR). Canonical transient receptor potential 3 (TRPC3) channels are integral to the propagation of seizures in SE, and vascular smooth muscle cell (VSMC) TRPC3 channels participate in vasoconstriction. Therefore, we hypothesize that cerebrovascular TRPC3 channels may contribute to seizure-induced IHR. To examine this possibility, we developed a smooth muscle-specific TRPC3 knockout (TRPC3smcKO) mouse. To quantify changes in neurovascular coupling, we combined laser speckle contrast imaging with simultaneous electroencephalogram recordings. Control mice exhibited multiple IHRs, and a limited increase in cerebral blood flow during SE with a high degree of moment-to-moment variability in which blood flow was not correlated with neuronal activity. In contrast, TRPC3smcKO mice showed a greater increase in blood flow that was less variable and was positively correlated with neuronal activity. Genetic ablation of smooth muscle TRPC3 channels shortened the duration of Se by eliminating a secondary phase of intense seizures, which was evident in littermate controls. Our results are consistent with the idea that TRPC3 channels expressed by cerebral VSMcs contribute to the iHR during Se, which is a critical factor in the progression of Se. Status epilepticus (SE) is a life-threatening condition characterized by continuous or rapidly repeating seizures 1. Attempts to understand the pathogenesis and progression of SE have historically focused on neuronal dysfunction, particularly hyperexcitation, rather than on a broader perspective that allows for the culpability of both neuronal and vascular abnormalities as contributors to SE. Blood flow is tightly coupled to the metabolic demands of local neuronal activity in a process termed neurovascular coupling, which is facilitated by highly complex interactions between neurons, glia, and vascular cells 2-5. Brain homeostasis and proper neuronal function fully rely on intact neurovascular coupling. Accepting this tenet, it is not surprising that disruption of neurovascular coupling is increasingly recognized as a shared feature of many neurological disorders, including epileptic seizures 2,3,6,7 , and cerebrovascular dysfunction may be a key feature of SE. Acute insults to the brain are widely reported to result in spreading depolarization 6,8-10 , or waves of neuronal depolarization emanating from the locus of the trauma and proceeding outwardly through healthy tissue. Such spreading depolarizations are observed clinically in traumatic brain injury 8,9 , stroke 9 , brain hemorrhage 6,9,10 , and epileptic seizure 6,9,10. Spreading depolarizations have been shown to induce a transient hyperperfusion of blood flow, which is often followed by one or more periods of hypoperfusion 6,8-10. This hypoperfusion, known as the inverse hemodynamic response (IHR), is thought to be mediated by vasoconstriction of small intracerebral arteries and arterioles 9,10....

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Section: Resultsmentioning

confidence: 86%

Section: Methodsmentioning

confidence: 99%

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Vascular smooth muscle TRPC3 channels facilitate the inverse hemodynamic response during status epilepticus

Cozart

Phelan

et al. 2020

Sci Rep

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“…29 Similar to our findings, pilocarpine-induced SE in mice increases theta activity in the preictal and SE phases. 30 In addition, case studies of patients diagnosed with idiopathic generalized epilepsy reveal increases in theta and delta power during interictal states. 31 Moving forward, it will be interesting to test in the ES1−/− mouse model of CWNA toxicity the hypothesis that drug treatments that reduce the observed increase in power of EEG activity in the 0.1-8 Hz frequency range would ameliorate chronic epileptic activity that follows prolonged benzodiazepine-resistant SE.…”

Section: Discussionmentioning

confidence: 99%

Soman‐induced status epilepticus, epileptogenesis, and neuropathology in carboxylesterase knockout mice treated with midazolam

Marrero‐Rosado¹,

Furtado²,

Schultz³

et al. 2018

Epilepsia

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SummaryObjectiveExposure to chemical warfare nerve agents (CWNAs), such as soman (GD), can induce status epilepticus (SE) that becomes refractory to benzodiazepines when treatment is delayed, leading to increased risk of epileptogenesis, severe neuropathology, and long‐term behavioral and cognitive deficits. Rodent models, widely used to evaluate novel medical countermeasures (MCMs) against CWNA exposure, normally express plasma carboxylesterase, an enzyme involved in the metabolism of certain organophosphorus compounds. To better predict the efficacy of novel MCMs against CWNA exposure in human casualties, it is crucial to use appropriate animal models that mirror the human condition. We present a comprehensive characterization of the seizurogenic, epileptogenic, and neuropathologic effects of GD exposure with delayed anticonvulsant treatment in the plasma carboxylesterase knockout (ES1−/−) mouse.MethodsElectroencephalography (EEG) electrode‐implanted ES1−/− and wild‐type (C57BL/6) mice were exposed to various seizure‐inducing doses of GD, treated with atropine sulfate and the oxime HI‐6 at 1 minute after exposure, and administered midazolam at 15‐30 minutes following the onset of seizure activity. The latency of acute seizure onset and spontaneous recurrent seizures (SRS) was assessed, as were changes in EEG power spectra. At 2 weeks after GD exposure, neurodegeneration and neuroinflammation were assessed.Results GD‐exposed ES1−/− mice displayed a dose‐dependent response in seizure severity. Only ES1−/− mice exposed to the highest tested dose of GD developed SE, subchronic alterations in EEG power spectra, and SRS. Degree of neuronal cell loss and neuroinflammation were dose‐dependent; no significant neuropathology was observed in C57BL/6 mice or ES1−/− mice exposed to lower GD doses.SignificanceThe US Food and Drug Administration (FDA) animal rule requires the use of relevant animal models for the advancement of MCMs against CWNAs. We present evidence that argues for the use of the ES1−/− mouse model to screen anticonvulsant, antiepileptic, and/or neuroprotective drugs against GD‐induced toxicity, as well as to identify mechanisms of GD‐induced epileptogenesis.

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“…TRPC3 channels are found to be responsible for pilocarpine-induced status epilepticus (SE) in mice. The reduction on SE in TRPC3 KO mice is caused by a selective attenuation of pilocarpine-induced theta wave activity [103]. TRPC7 can be detected in CA3 pyramidal neurons largely.…”

Section: Canonical Transient Receptor Potential (Trpc)mentioning

confidence: 92%

Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability

Zhang¹,

Zhu²,

Cheng³

et al. 2019

Epilepsy - Advances in Diagnosis and Therapy

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Voltage-gated ion channels (VGICs), extensively distributed in the central nervous system (CNS), are responsible for the generation as well as modulation of neuroexcitability and considered as vital players in the pathogenesis of human epilepsy, with regulating the shape and duration of action potentials (APs). For instance, genetic alterations or abnormal expression of voltage-gated sodium channels (VGSCs), Kv channels, and voltage-gated calcium channels (VGCCs) are proved to be associated with epileptogenesis. This chapter aims to highlight recent discoveries on the mutations in VGIC genes and dysfunction of VGICs in epilepsy, especially focusing on the pathophysiological and pharmacological properties. Understanding the role of epilepsy-associated VGICs might not only contribute to clarify the mechanism of epileptogenesis and genetic modifiers but also provide potential targets for the precise treatment of epilepsy.

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TRPC3 channels play a critical role in the theta component of pilocarpine‐induced status epilepticus in mice

Cited by 28 publications

References 28 publications

Vascular smooth muscle TRPC3 channels facilitate the inverse hemodynamic response during status epilepticus

Vascular smooth muscle TRPC3 channels facilitate the inverse hemodynamic response during status epilepticus

Soman‐induced status epilepticus, epileptogenesis, and neuropathology in carboxylesterase knockout mice treated with midazolam

Ion Channels in Epilepsy: Blasting Fuse for Neuronal Hyperexcitability

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