Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex

Short, Brittany Parker; Kozek, Lindsay; Harmsen, Hannah; Zhang, Bo; Wong, Michael; Ess, Kevin C.; Fu, Changlin; Naftel, Robert P.; Pearson, Matthew M.; Carson, Robert P.

doi:10.1016/j.nbd.2019.05.003

Cited by 7 publications

(6 citation statements)

References 33 publications

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“…Its implication in epileptogenesis is based on increased extracellular potassium upon neuronal depolarization, reduced astrocytic clearance of excess potassium, and consequently neuronal hyperexcitability and seizures. Key players in astrocytic potassium buffering represent aquaporins, Kirs, and connexins, which all display dysregulation in TSC-null astrocytes, Tsc1 GFAP mice, and surgically resected TSC tissue ( 84 – 87 ). Another well-established player in neuronal hyperexcitability is impaired astrocyte-mediated clearance of glutamate, which can predispose neurons to sustained excitability, excitotoxicity, and epileptiform activity.…”

Section: Astrocytesmentioning

confidence: 99%

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

et al. 2020

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Tuberous sclerosis complex (TSC) represents the prototypic monogenic disorder of the mammalian target of rapamycin (mTOR) pathway dysregulation. It provides the rational mechanistic basis of a direct link between gene mutation and brain pathology (structural and functional abnormalities) associated with a complex clinical phenotype including epilepsy, autism, and intellectual disability. So far, research conducted in TSC has been largely neuron-oriented. However, the neuropathological hallmarks of TSC and other malformations of cortical development also include major morphological and functional changes in glial cells involving astrocytes, oligodendrocytes, NG2 glia, and microglia. These cells and their interglial crosstalk may offer new insights into the common neurobiological mechanisms underlying epilepsy and the complex cognitive and behavioral comorbidities that are characteristic of the spectrum of mTOR-associated neurodevelopmental disorders. This review will focus on the role of glial dysfunction, the interaction between glia related to mTOR hyperactivity, and its contribution to epileptogenesis in TSC. Moreover, we will discuss how understanding glial abnormalities in TSC might give valuable insight into the pathophysiological mechanisms that could help to develop novel therapeutic approaches for TSC or other pathologies characterized by glial dysfunction and acquired mTOR hyperactivation.

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Section: Astrocytesmentioning

confidence: 99%

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

et al. 2020

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“…Subsequently, dysregulation of B and T lymphocytes may lead to abnormal responses and increase the risk for autoimmunity. 2 , 8 Furthermore, Short and colleagues 9 demonstrated increased AQP4-IgG expression by dysfunctional astrocytes in both TSC epileptogenic cortex and astrocyte culture models. As AQP4-IgG is a crucial antibody for the pathogenesis of NMOSD, it is tempting to speculate that the risk for NMOSD may increase in TSC population.…”

Section: Discussionmentioning

confidence: 99%

Neuromyelitis Optica in a Young Woman With Tuberous Sclerosis: Is There an Association?

Elkhooly

Rube

Sirvastava

et al. 2022

Journal of Investigative Medicine High Impact Case Reports

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Tuberous sclerosis complex (TSC) is a genetic neurocutaneous disorder that presents with multi-organ involvement, including but not limited to hamartomas in the brain, eyes, heart, lung, liver, kidney, and skin. Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory, autoimmune, demyelinating, central nervous system disorder, targeting the optic nerves and spinal cord. We report a 30-year-old woman with TSC who developed tingling in the legs that gradually involved her abdomen. Additional symptoms included severe vomiting that lasted for a week and spasms in her legs. One month later, she was hospitalized due to difficulty ambulating and tingling in her hands. Magnetic resonance imaging (MRI) of her spine showed longitudinally extensive upper cervical and lower thoracic cord signal changes. MRI scan of her brain showed few non-specific T2 signal changes along with cortical and subcortical tubers. Aquaporin (AQP4) IgG antibody was found to be positive in both serum and cerebrospinal fluid. Accordingly, she was diagnosed with NMOSD, treated with a 5-day course of intravenous steroids, followed by 5 sessions of plasma exchange. After her initial improvement, she was started on rituximab as maintenance therapy. Two years later, she is clinically stable, and her follow-up MRI showed marked improvement.

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“…According to the research findings on animal models, the expression of AQP4 protein would return to the baseline level at this period, speculating that equal quantities of AQP4 may be found in chronic epilepsy patients and healthy controls, which may be an explanation for our results. Kir4.1 and AQP4 are involved tightly with the regulation of water, potassium redistribution and volume of ECS in the CNS, 24 and play an important role in regulating the excitability of neurons. In the CA1 region of the hippocampus of mice knocked out by the AQP4 gene, potassium clearance was delayed, indicating that AQP4 and Kir4.1 not only co-expressed in the same region, but were also closely related in function.…”

Section: Discussionmentioning

confidence: 99%

<p>Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy</p>

Zhu¹,

Zhang²,

Fu³

et al. 2020

NDT

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Background and Purpose: Epilepsy is a common chronic neurological disorder. About one third of epilepsy patients will suffer from drug resistance after rational selection of antiepileptic drug treatment. The formation of drug-resistant epilepsy has quite a few causes of which genetic factors are considered to be the most important. Previous studies have suggested that the aquaporin 4(AQP4) and inward rectifier potassium ion channel Kir4.1 (encoded by gene KCNJ10) may act in concert to adjust water homeostasis and concentration of potassium ions in extracellular spaces of the central nervous system. Therefore, these two molecules would play a major role in the regulation of the excitability of neurons. In order to explore the potential mechanism of genetic factors related to AQP4 and Kir4.1, we conducted a study to analyze the effects of the AQP4 and KCNJ10 genes' single nucleotide polymorphisms (SNPs) on epileptic drug resistance and seizure susceptibility in a group of Chinese Han patients with focal epilepsy. Materials and Methods: In total, 510 patients with focal-onset seizures and 206 healthy controls were recruited. Among the patients, 222 were drug resistant and 288 were responsive. The selection of tag SNPs was based on the Hapmap database and Haploview software. Genotyping of three loci of the AQP4 gene (rs1058424, rs3763043 and rs35931) and nine loci of the KCNJ10 gene (rs12122979, rs1186685, rs6690889, rs2486253, rs1186675, rs12402969, rs12729701, rs1890532 and rs3795339) was conducted on the Sequenom MassARRAY iPLEX platform. Results: The distribution of genotype and allele frequencies of selected SNP loci of AQP4 and KCNJ10 genes showed no significant difference between the drug-resistant and drugresponsive groups (p>0.05), and no significant difference between all the idiopathic focal epilepsy patients and healthy controls either. Conclusion: AQP4 and KCNJ10 genetic polymorphisms may not be associated with drug resistance or seizure susceptibility of focal epilepsy in the Chinese Han population.

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Cerebral aquaporin-4 expression is independent of seizures in tuberous sclerosis complex

Cited by 7 publications

References 33 publications

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

Neuromyelitis Optica in a Young Woman With Tuberous Sclerosis: Is There an Association?

<p>Effects of AQP4 and KCNJ10 Gene Polymorphisms on Drug Resistance and Seizure Susceptibility in Chinese Han Patients with Focal Epilepsy</p>

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