KCC2 function modulates in vitro ictogenesis

Hamidi, Shabnam; Avoli, Massimo

doi:10.1016/j.nbd.2015.04.006

Cited by 61 publications

(65 citation statements)

References 30 publications

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“…Contrary to our findings, recent work with the 4-AP model described that reduced KCC2 function by VU0240511 is anti-ictogenic in rat entorhinal-hippocampal slices (Hamidi and Avoli, 2015). This result could be due to a mischaracterization of continous epileptiform events, which were described as continuous interictal events without ictal events.…”

Section: Discussioncontrasting

confidence: 99%

Compromising KCC2 transporter activity enhances the development of continuous seizure activity

et al. 2016

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Impaired neuronal inhibition has long been associated with the increased probability of seizure occurrence and heightened seizure severity. Fast synaptic inhibition in the brain is primarily mediated by the type A γ-aminobutyric acid receptors (GABAARs), ligand-gated ion channels that can mediate Cl− influx resulting in membrane hyperpolarization and the restriction of neuronal firing. In most adult brain neurons, the K+/Cl− co-transporter-2 (KCC2) establishes hyperpolarizing GABAergic inhibition by maintaining low [Cl−]i. In this study, we sought to understand how decreased KCC2 transport function affects seizure event severity. We impaired KCC2 transport in the 0-Mg2+ ACSF and 4-aminopyridine in vitro models of epileptiform activity in acute mouse brain slices. Experiments with the selective KCC2 inhibitor VU0463271 demonstrated that reduced KCC2 transport increased the duration of SLEs, resulting in non-terminating discharges of clonic-like activity. We also investigated slices obtained from the KCC2-Ser940Ala (S940A) point-mutant mouse, which has a mutation at a known functional phosphorylation site causing behavioral and cellular deficits under hyperexcitable conditions. We recorded from the entorhinal cortex of S940A mouse brain slices in both 0-Mg2+ ACSF and 4-aminopyridine, and demonstrated that loss of the S940 residue increased the susceptibility of continuous clonic-like discharges, an in vitro form of status epilepticus. Our experiments revealed KCC2 transport activity is a critical factor in seizure event duration and mechanisms of termination. Our results highlight the need for therapeutic strategies that potentiate KCC2 transport function in order to decrease seizure event severity and prevent the development of status epilepticus.

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Section: Discussioncontrasting

confidence: 99%

Compromising KCC2 transporter activity enhances the development of continuous seizure activity

et al. 2016

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“…However, application of a cation-chloride cotransporter antagonist bumetanide (50μM, similar to that used in Hamidi and Avoli 21 ) failed to reduce H 2 O 2 release and to prevent either the DC shift or SLE induction by stimulation (n = 3; see Fig 2C). 21,23 Finally, inhibition of GABAergic transmission by bicuculline (20μM) did not block spontaneous SLEs (n = 3; see Fig 2D), indicating that network synchronization by GABAergic neurotransmission is not mandatory for the SLE initiation. 21,23 Finally, inhibition of GABAergic transmission by bicuculline (20μM) did not block spontaneous SLEs (n = 3; see Fig 2D), indicating that network synchronization by GABAergic neurotransmission is not mandatory for the SLE initiation.…”

Section: Glutamate-induced Activation Of Nicotinamide Adenine Dinuclementioning

confidence: 87%

Activation of nicotinamide adenine dinucleotide phosphate oxidase is the primary trigger of epileptic seizures in rodent models

Malkov

Ivanov

Latyshkova

et al. 2019

Annals of Neurology

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Objective: Despite decades of epilepsy research, 30% of focal epilepsies remain resistant to antiseizure drugs, with effective drug development impeded by lack of understanding on how seizures are initiated. Here, we report the mechanism of seizure onset relevant to most seizures that are characteristic of focal epilepsies. Methods: Electric and metabolic network parameters were measured using several seizure models in mouse hippocampal slices and acutely induced seizures in rats in vivo to determine metabolic events occurring at seizure onset. Results: We show that seizure onset is associated with a rapid release of H 2 O 2 resulting from N-methyl-D-aspartate (NMDA) receptor-mediated activation of nicotinamide adenine dinucleotide phosphate oxidase (NOX). NOX blockade prevented the fast H 2 O 2 release as well as the direct current shift and seizurelike event induction in slices. Similarly, intracerebroventricular injection of NOX antagonists prevented acutely induced seizures in rats. Interpretation: Our results show that seizures are initiated by NMDA receptor-mediated NOX-induced oxidative stress and can be arrested by NOX inhibition. We introduce a novel use for blood-brain barrier-permeable NOX inhibitor with a significant potential to become the first seizure-specific medication. Thus, targeting NOX may provide a breakthrough treatment for focal epilepsies. ANN NEUROL 2019;85:907-920 A major goal of contemporary epilepsy research is the View this article online at wileyonlinelibrary.com.

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“…43 The mechanism by which the specific excitatory/inhibitory imbalance at LVF onset promotes seizure genesis is not yet resolved but may involve depolarizing GABAergic activity 45 or potassium and chloride efflux due to activation of the KCC2 cotransporter. 46,47 It is possible that novel pharmacological interventions could reduce inhibitory interneuron overactivation and thereby prevent seizure evolution.…”

Section: Discussionmentioning

confidence: 99%