Molecular Mechanisms of Epilepsy: The Role of the Chloride Transporter KCC2

Belperio, Giorgio; Corso, Christopher D.; Duarte, Carlos B.; Mele, Miranda

doi:10.1007/s12031-022-02041-7

Cited by 3 publications

(3 citation statements)

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“…29,30 For example, it has been proposed that the excitatoryinhibitory imbalance of epilepsy may be coupled in certain conditions to the dysregulation of γ aminobutyric acid (GABA) neurotransmission, the main inhibitory signal in the brain. 31 Additionally, the inhibitory signaling by GABA relies on the Cl-gradient across the plasma membrane. 32 Altered glial potassium homeostasis is also associated with increased susceptibility to epilepsy.…”

Section: Discussionmentioning

confidence: 99%

“…This may be related to the mechanisms in epileptogenesis of dysfunction of structures responsible for maintaining ionic homeostasis 29,30 . For example, it has been proposed that the excitatory‐inhibitory imbalance of epilepsy may be coupled in certain conditions to the dysregulation of γ aminobutyric acid (GABA) neurotransmission, the main inhibitory signal in the brain 31 . Additionally, the inhibitory signaling by GABA relies on the Cl‐ gradient across the plasma membrane 32 .…”

Section: Discussionmentioning

confidence: 99%

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Differentiation of epilepsy and psychogenic nonepileptic events based on body fluid characteristics

Xia

Lai

et al. 2023

Epilepsia Open

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ObjectiveDifferential diagnosis between epileptic seizures and psychogenic nonepileptic events (PNEEs) is a worldwide problem for neurologists. The present study aims to identify important characteristics from body fluid tests and develop diagnostic models based on them.MethodsThis is a register‐based observational study in patients with a diagnosis of epilepsy or PNEEs at West China Hospital of Sichuan University. Data from body fluid tests between 2009 and 2019 were used as a training set. We constructed models with a random forest approach in eight training subsets divided by sex and categories of tests, including electrolyte, blood cell, metabolism, and urine tests. Then, we collected data prospectively from patients between 2020 and 2022 to validate our models and calculated the relative importance of characteristics in robust models. Selected characteristics were finally analyzed with multiple logistic regression to establish nomograms.ResultsA total of 388 patients, including 218 with epilepsy and 170 with PNEEs, were studied. The AUROCs of random forest models of electrolyte and urine tests in the validation phase achieved 80.0% and 79.0%, respectively. Carbon dioxide combining power, anion gap, potassium, calcium, and chlorine in electrolyte tests and specific gravity, pH, and conductivity in urine tests were selected for the logistic regression analysis. C (ROC) of the electrolyte and urine diagnostic nomograms achieved 0.79 and 0.85, respectively.SignificanceThe application of routine indicators of serum and urine may help in the more accurate identification of epileptic and PNEEs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differentiation of epilepsy and psychogenic nonepileptic events based on body fluid characteristics

Xia

Lai

et al. 2023

Epilepsia Open

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“…122 Reduced expression of KCC2 disrupts the E/I balance causing brain dysfunction, including intractable epilepsy. [125][126][127][128][129] Indeed, KCC2 mutations that impair extrusion of Cl − humans result in severe seizures in mice and in humans [130][131][132] and are associated with schizophrenia and ASD. 130 Similarly, psychological stress and neuroinflammation during early prenatal development reduce KCC2 expression delaying the E/I GABA shift, which has been implicated in neurodevelopmental and psychiatric disorders.…”

Section: Potential Common Effectorsmentioning

confidence: 99%

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

D’Mello

2023

Exp Biol Med (Maywood)

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Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.

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