Regulation of the cell surface expression of chloride transporters during epileptogenesis

González, Marco I.

doi:10.1016/j.neulet.2016.06.042

Cited by 11 publications

(3 citation statements)

References 28 publications

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“…Post Traumatic Epilepsy: Richard Miles and colleagues demonstrated that GABA A receptor activation could be excitatory in human brain tissue resected for control of medically intractable epilepsy (Cohen et al ., 2002). However, the pathomechanism has never been elucidated (Huberfeld et al ., 2007; González, 2016; Karlócai et al ., 2016). Gliosis is the most common finding in medically intractable epilepsy (Thom, 2014).…”

Section: Discussionmentioning

confidence: 99%

Displacement of extracellular chloride by immobile anionic constituents of the brain’s extracellular matrix

Normoyle

Staley

2022

Preprint

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GABA is the primary inhibitory neurotransmitter. Membrane currents evoked by GABAAreceptor activation have uniquely small driving forces: their reversal potential (EGABA) is very close to the resting membrane potential. As a consequence, GABAAcurrents can flow in either direction, depending on both the membrane potential and the local intra and extracellular concentrations of the primary permeant ion, chloride (Cl). Cytoplasmic Cl concentrations vary widely due to displacement of mobile Cl ions by relatively immobile anions. Here we describe new reporters of extracellular chloride (Cl-o) and demonstrate that Cl is displaced in the extracellular space by high and spatially heterogenous concentrations of sulfated glycosaminoglycans. The mean Cl-ois only half the canonical concentration, i.e. the Cl concentration in the cerebrospinal fluid. Cl-omicrodomains provide a mechanism to link the highly stable distribution of GAGs in the brain’s extracellular space to neuronal signal processing via the effects on the amplitude and direction of GABAAtransmembrane Cl currents.

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Section: Discussionmentioning

confidence: 99%

Displacement of extracellular chloride by immobile anionic constituents of the brain’s extracellular matrix

Normoyle

Staley

2022

Preprint

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“…A single chemoconvulsant-induced seizure episode during P5-7 may result in an upregulation of KCC2 (Khirug et al, 2010) in a non-SE model. This is in contrast to downregulation of KCC2 seen in an adult SE model (Gonzalez, 2016). This study characterized pentylenetetrazole (PTZ)-induced neonatal seizures in CD-1 pups at P7 to determine their response to PB and BTN, to investigate the role of the TrkB pathway and associated KCC2 functional modulation.…”

Section: Introductionmentioning

confidence: 97%

Pharmaco‐resistant Neonatal Seizures: Critical Mechanistic Insights from a Chemoconvulsant Model

Kharod

Carter

Kadam

2018

Developmental Neurobiology

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Neonatal seizures are harmful to the developing brain and are associated with mortality and long-term neurological comorbidities. Hypoxic-ischemic encephalopathy (HIE) seizures represent a significant proportion of such seizures. Phenobarbital (PB) remains the first line anti-seizure drug (ASD) treatment but fails ~50% of the time. Translational models of neonatal seizures are crucial to investigating mechanisms underlying PB-resistance. A model of PB-resistant ischemic seizures in postnatal day 7 (P7) CD-1 mice reported K-Cl cotransporter 2 (KCC2) degradation that has been shown to be due to activation of the TrkB pathway. We investigated PB-efficacy in a pentylenetetrazole (PTZ) model of neonatal seizures in the same strain and age using identical treatment protocols to gain insights into mechanisms underlying PB-resistance. A single dose of PTZ (80 mg/kg; IP) consistently induced repetitive seizures that did not progress to status epilepticus (SE). PB (25 mg/kg; IP, single dose) significantly suppressed the PTZ-induced seizures. This was associated with significant KCC2 upregulation and stable Na-K-Cl cotransporter 1 (NKCC1) expression at 24h. The TrkB pathway was not activated. PTZ seizure burdens were significantly higher than those reported for ischemic seizures, indicating seizure severity did not dictate the differences in PB-efficacy. Bumetanide (BTN) (0.1-0.2 mg/kg; IP) did not work as an anti-seizure agent, similar to the ischemic model. When investigating mechanisms underlying the emergence of PB-resistance in translational models, the method by which seizures are induced may dictate mechanisms underlying emergence of PB-resistance.

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“…KCC2 down-regulation weakens KCC2 function and GABA inhibition, in turn, accelerates and facilitates seizure induction (Munakata et al, 2007 ; Eftekhari et al, 2014 ; Hübner, 2014 ; Kahle et al, 2014 , 2016 ; Karlócai et al, 2016 ; Chen et al, 2017 ). However, the mechanism of seizure-induced KCC2 down-regulation remains inconclusive despite the abundance of studies on seizure development (Li et al, 2008 ; Puskarjov et al, 2015 ; González, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

M-Calpain Activation Facilitates Seizure Induced KCC2 Down Regulation

Wan

Ren

Chen

et al. 2018

Front. Mol. Neurosci.

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Potassium chloride co-transporter 2 (KCC2), a major chloride transporter that maintains GABAA receptor inhibition in mature mammalian neurons, is down-regulated in the hippocampus during epileptogenesis. Impaired KCC2 function accelerates or facilitates seizure onset. Calpain, with two main subtypes of m- and μ-calpain, is a Ca2+-dependent cysteine protease that mediates the nonlysosomal degradation of KCC2. Although recent studies have demonstrated that calpain inhibitors exert antiepileptic and neuroprotective effects in animal models of acute and chronic epilepsy, whether calpain activation affects seizure induction through KCC2 degradation remains unknown. Our results showed that: (1) Blockade of calpain by non-selective calpain inhibitor MDL-28170 prevented convulsant stimulation induced KCC2 downregulation, and reduced the incidence and the severity of pentylenetetrazole (PTZ) induced seizures. (2) m-calpain, but not μ-calpain, inhibitor mimicked MDL-28170 effect on preventing KCC2 downregulation. (3) Phosphorylation of m-calpain has been significantly enhanced during seizure onset, which was partly mediated by the calcium independent MAPK/ERK signaling pathway activation. (4) MAPK/ERK signaling blockade also had similar effect as total calpain blockade on both KCC2 downregulation and animal seizure induction. The results indicate that upregulated m-calpain activation by MAPK/ERK during convulsant stimulation down regulates both cytoplasm- and membrane KCC2, and in turn facilitates seizure induction. This finding may provide a foundation for the development of highly effective antiepileptic drugs targeting of m-calpain.

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Regulation of the cell surface expression of chloride transporters during epileptogenesis

Cited by 11 publications

References 28 publications

Displacement of extracellular chloride by immobile anionic constituents of the brain’s extracellular matrix

Displacement of extracellular chloride by immobile anionic constituents of the brain’s extracellular matrix

Pharmaco‐resistant Neonatal Seizures: Critical Mechanistic Insights from a Chemoconvulsant Model

M-Calpain Activation Facilitates Seizure Induced KCC2 Down Regulation

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