Quinine suppresses extracellular potassium transients and ictal epileptiform activity without decreasing neuronal excitability in vitro

Conventional neural networks are characterized by many neurons coupled together through synapses. The activity, synchronization, plasticity and excitability of the network are then controlled by its synaptic connectivity. Neurons are surrounded by an extracellular space whereby fluctuations in specific ionic concentration can modulate neuronal excitability. Extracellular concentrations of potassium ([K + ] o ) can generate neuronal hyperexcitability. Yet, after many years of research, it is still unknown whether an elevation of potassium is the cause or the result of the generation, propagation and synchronization of epileptiform activity. An elevation of potassium in neural tissue can be characterized by dispersion (global elevation of potassium) and lateral diffusion (local spatial gradients). Both experimental and computational studies have shown that lateral diffusion is involved in the generation and the propagation of neural activity in diffusively coupled networks. Therefore, diffusion-based coupling by potassium can play an important role in neural networks and it is reviewed in four sections. Section 2 shows that potassium diffusion is responsible for the synchronization of activity across a mechanical cut in the tissue. A computer model of diffusive coupling shows that potassium diffusion can mediate communication between cells and generate abnormal and/or periodic activity in small (§3) and in large networks of cells (§4). Finally, in §5, a study of the role of extracellular potassium in the propagation of axonal signals shows that elevated potassium concentration can block the propagation of neural activity in axonal pathways. Taken together, these results indicate that potassium accumulation and diffusion can interfere with normal activity and generate abnormal activity in neural networks.

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Conditions Sufficient for Nonsynaptic Epileptogenesis in the CA1 Region of Hippocampal Slices

Journal of Neurophysiology ◽

10.1152/jn.00196.2001 ◽

2002 ◽

Vol 87 (1) ◽

pp. 62-71 ◽

Cited By ~ 27

Author(s):

Marom Bikson ◽

Scott C. Baraban ◽

Dominique M. Durand

Keyword(s):

Neuronal Excitability ◽

Epileptiform Activity ◽

Hippocampal Slices ◽

Seizure Threshold ◽

Ion Selective Electrodes ◽

Receptor Antagonists ◽

Sodium Conductance ◽

Ca1 Region ◽

Persistent Sodium Conductance

Nonsynaptic mechanisms exert a powerful influence on seizure threshold. It is well-established that nonsynaptic epileptiform activity can be induced in hippocampal slices by reducing extracellular Ca2+ concentration. We show here that nonsynaptic epileptiform activity can be readily induced in vitro in normal (2 mM) Ca2+ levels. Those conditions sufficient for nonsynaptic epileptogenesis in the CA1 region were determined by pharmacologically mimicking the effects of Ca2+ reduction in normal Ca2+ levels. Increasing neuronal excitability, by removing extracellular Mg2+ and increasing extracellular K+ (6–15 mM), induced epileptiform activity that was suppressed by postsynaptic receptor antagonists [d-(−)-2-amino-5-phosphonopentanoic acid, picrotoxin, and 6,7-dinitroquinoxaline-2,3-dione] and was therefore synaptic in nature. Similarly, epileptiform activity induced when neuronal excitability was increased in the presence of KCaantagonists (verruculogen, charybdotoxin, norepinephrine, tetraethylammonium salt, and Ba2+) was found to be synaptic in nature. Decreases in osmolarity also failed to induce nonsynaptic epileptiform activity in the CA1 region. However, increasing neuronal excitability (by removing extracellular Mg2+ and increasing extracellular K+) in the presence of Cd2+, a nonselective Ca2+channel antagonist, or veratridine, a persistent sodium conductance enhancer, induced spontaneous nonsynaptic epileptiform activity in vitro. Both novel models were characterized using intracellular and ion-selective electrodes. The results of this study suggest that reducing extracellular Ca2+ facilitates bursting by increasing neuronal excitability and inhibiting Ca2+ influx, which might, in turn, enhance a persistent sodium conductance. Furthermore, these data show that nonsynaptic mechanisms can contribute to epileptiform activity in normal Ca2+ levels.

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Diadenosine-Polyphosphate Analogue AppCH2ppA Suppresses Seizures by Enhancing Adenosine Signaling in the Cortex

Cerebral Cortex ◽

10.1093/cercor/bhy257 ◽

2018 ◽

Vol 29 (9) ◽

pp. 3778-3795

Author(s):

Alexandre Pons-Bennaceur ◽

Vera Tsintsadze ◽

Thi-thien Bui ◽

Timur Tsintsadze ◽

Marat Minlebaev ◽

...

Keyword(s):

Human Population ◽

Temporal Summation ◽

Neuronal Excitability ◽

Epileptiform Activity ◽

Treatment Strategies ◽

Anticonvulsant Treatment ◽

A1 Receptor ◽

Adenosine Signaling

Abstract Epilepsy is a multifactorial disorder associated with neuronal hyperexcitability that affects more than 1% of the human population. It has long been known that adenosine can reduce seizure generation in animal models of epilepsies. However, in addition to various side effects, the instability of adenosine has precluded its use as an anticonvulsant treatment. Here we report that a stable analogue of diadenosine-tetraphosphate: AppCH2ppA effectively suppresses spontaneous epileptiform activity in vitro and in vivo in a Tuberous Sclerosis Complex (TSC) mouse model (Tsc1+/−), and in postsurgery cortical samples from TSC human patients. These effects are mediated by enhanced adenosine signaling in the cortex post local neuronal adenosine release. The released adenosine induces A1 receptor-dependent activation of potassium channels thereby reducing neuronal excitability, temporal summation, and hypersynchronicity. AppCH2ppA does not cause any disturbances of the main vital autonomous functions of Tsc1+/− mice in vivo. Therefore, we propose this compound to be a potent new candidate for adenosine-related treatment strategies to suppress intractable epilepsies.

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2-Deoxy-d-glucose reduces epileptiform activity by presynaptic mechanisms

Journal of Neurophysiology ◽

10.1152/jn.00723.2018 ◽

2019 ◽

Vol 121 (4) ◽

pp. 1092-1101 ◽

Cited By ~ 3

Author(s):

Yu-Zhen Pan ◽

Thomas P. Sutula ◽

Paul A. Rutecki

Keyword(s):

Pyramidal Neurons ◽

Epileptiform Activity ◽

Network Activity ◽

Membrane Properties ◽

Extracellular Potassium ◽

Acute Effects ◽

Postsynaptic Currents ◽

Neuronal Network Activity ◽

Presynaptic Mechanisms

2-Deoxy-d-glucose (2DG), a glucose analog that inhibits glycolysis, has acute and chronic antiepileptic effects. We evaluated 2DG’s acute effects on synaptic and membrane properties of CA3 pyramidal neurons in vitro. 2DG (10 mM) had no effects on spontaneously occurring postsynaptic currents (PSCs) in 3.5 mM extracellular potassium concentration ([K+]o). In 7.5 mM [K+]o, 2DG significantly reduced the frequency of epileptiform bursting and the charge carried by postsynaptic currents (PSCs) with a greater effect on inward excitatory compared with outward inhibitory charge (71% vs. 40%). In 7.5 mM [K+]o and bicuculline, 2DG reduced significantly the excitatory charge by 67% and decreased the frequency but not amplitude of excitatory PSCs between bursts. In 7.5 mM [K+]o, 2DG reduced pharmacologically isolated inhibitory PSC frequency without a change in amplitude. The frequency but not amplitude of inward miniature PSCs was reduced when 2DG was applied in 7.5 mM [K+]o before bath application of TTX, but there was no effect when 2DG was applied after TTX, indicating a use-dependent uptake of 2DG was required for its actions at a presynaptic locus. 2DG did not alter membrane properties of CA3 neurons except for reducing the slow afterhyperpolarization in 3.5 but not 7.5 mM [K+]o. The reduction in frequency of spontaneous and inward miniature PSCs in elevated [K+]o indicates a presynaptic mechanism of action. 2DG effects required use-dependent uptake and suggest an important role for glycolysis in neuronal metabolism and energetics in states of high neural activity as occur during abnormal network synchronization and seizures. NEW & NOTEWORTHY 2-Deoxy-d-glucose (2DG) is a glycolytic inhibitor and suppresses epileptiform activity acutely and has chronic antiepileptic effects. The mechanisms of the acute effects are not well delineated. In this study, we show 2DG suppressed abnormal network epileptiform activity without effecting normal synaptic network activity or membrane properties. The effects appear to be use dependent and have a presynaptic locus of action. Inhibition of glycolysis is a novel presynaptic mechanism to limit abnormal neuronal network activity and seizures.

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Extracellular Potassium and Seizures: Excitation, Inhibition and the Role of Ih

International Journal of Neural Systems ◽

10.1142/s0129065716500441 ◽

2016 ◽

Vol 26 (08) ◽

pp. 1650044 ◽

Cited By ~ 5

Author(s):

Lihua Wang ◽

Suzie Dufour ◽

Taufik A. Valiante ◽

Peter L. Carlen

Keyword(s):

Neuronal Excitability ◽

Seizure Activity ◽

Membrane Properties ◽

Resting Membrane Potential ◽

Extracellular Potassium ◽

Hcn Channels ◽

Extracellular Potassium Concentration ◽

Prolonged Seizure

Seizure activity leads to increases in extracellular potassium concentration ([K[Formula: see text]]o), which can result in changes in neuronal passive and active membrane properties as well as in population activities. In this study, we examined how extracellular potassium modulates seizure activities using an acute 4-AP induced seizure model in the neocortex, both in vivo and in vitro. Moderately elevated [K[Formula: see text]]o up to 9[Formula: see text]mM prolonged seizure durations and shortened interictal intervals as well as depolarized the neuronal resting membrane potential (RMP). However, when [K[Formula: see text]]o reached higher than 9[Formula: see text]mM, seizure like events (SLEs) were blocked and neurons went into a depolarization-blocked state. Spreading depression was never observed as the blockade of ictal events could be reversed within 1–2[Formula: see text]min after the raised [K[Formula: see text]]o was changed back to control levels. This concentration-dependent dual effect of [K[Formula: see text]]o was observed using in vivo and in vitro mouse brain preparations as well as in human neocortical tissue resected during epilepsy surgery. Blocking the Ih current, mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, modulated the elevated [K[Formula: see text]]o influence on SLEs by promoting the high [K[Formula: see text]]o inhibitory actions. These results demonstrate biphasic actions of raised [K[Formula: see text]]o on neuronal excitability and seizure activity.

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Discovery of a small molecule modulator of the Kv1.1/Kvβ1 channel complex that reduces neuronal excitability and in vitro epileptiform activity

CNS Neuroscience & Therapeutics ◽

10.1111/cns.13060 ◽

2018 ◽

Vol 25 (4) ◽

pp. 442-451 ◽

Cited By ~ 6

Author(s):

Isabelle Niespodziany ◽

Brice Mullier ◽

Véronique Marie André ◽

Philippe Ghisdal ◽

Eric Jnoff ◽

...

Keyword(s):

Small Molecule ◽

Neuronal Excitability ◽

Epileptiform Activity ◽

Small Molecule Modulator

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Dynamics of high-frequency synchronization during seizures

Journal of Neurophysiology ◽

10.1152/jn.00761.2012 ◽

2013 ◽

Vol 109 (10) ◽

pp. 2423-2437 ◽

Cited By ~ 7

Author(s):

Giri P. Krishnan ◽

Gregory Filatov ◽

Maxim Bazhenov

Keyword(s):

High Frequency ◽

Epileptiform Activity ◽

Epileptic Seizures ◽

Temporal Analysis ◽

Neuronal Firing ◽

Extracellular Potassium ◽

Epileptiform Discharges ◽

Baseline Activity ◽

High Frequency Activity

Pathological synchronization of neuronal firing is considered to be an inherent property of epileptic seizures. However, it remains unclear whether the synchrony increases for the high-frequency multiunit activity as well as for the local field potentials (LFPs). We present spatio-temporal analysis of synchronization during epileptiform activity using wide-band (up to 2,000 Hz) spectral analysis of multielectrode array recordings at up to 60 locations throughout the mouse hippocampus in vitro. Our study revealed a prominent structure of LFP profiles during epileptiform discharges, triggered by elevated extracellular potassium, with characteristic distribution of current sinks and sources with respect to anatomical structure. The cross-coherence of high-frequency activity (500–2,000 Hz) across channels was reduced during epileptic bursts compared with baseline activity and showed the opposite trend for lower frequencies. Furthermore, the magnitude of cross-coherence during epileptiform activity was dependent on distance: electrodes closer to the epileptic foci showed increased cross-coherence and electrodes further away showed reduced cross-coherence for high-frequency activity. These experimental observations were re-created and supported in a computational model. Our study suggests that different intrinsic and synaptic processes can mediate paroxysmal synchronization at low, medium, and high frequencies.

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Calcium-Activated Afterhyperpolarizations Regulate Synchronization and Timing of Epileptiform Bursts in Hippocampal CA3 Pyramidal Neurons

Journal of Neurophysiology ◽

10.1152/jn.00434.2006 ◽

2006 ◽

Vol 96 (6) ◽

pp. 3028-3041 ◽

Cited By ~ 32

Author(s):

David Fernández de Sevilla ◽

Julieta Garduño ◽

Emilio Galván ◽

Washington Buño

Keyword(s):

Neuronal Excitability ◽

Pyramidal Neurons ◽

Epileptiform Activity ◽

Network Activity ◽

Cellular Mechanisms ◽

Burst Frequency ◽

Potassium Conductances ◽

Hippocampal Ca3 ◽

Ca3 Pyramidal Neurons

Calcium-activated potassium conductances regulate neuronal excitability, but their role in epileptogenesis remains elusive. We investigated in rat CA3 pyramidal neurons the contribution of the Ca2+-activated K+-mediated afterhyperpolarizations (AHPs) in the genesis and regulation of epileptiform activity induced in vitro by 4-aminopyridine (4-AP) in Mg2+-free Ringer. Recurring spike bursts terminated by prolonged AHPs were generated. Burst synchronization between CA3 pyramidal neurons in paired recordings typified this interictal-like activity. A downregulation of the medium afterhyperpolarization (mAHP) paralleled the emergence of the interictal-like activity. When the mAHP was reduced or enhanced by apamin and EBIO bursts induced by 4-AP were increased or blocked, respectively. Inhibition of the slow afterhyperpolarization (sAHP) with carbachol, t-ACPD, or isoproterenol increased bursting frequency and disrupted burst regularity and synchronization between pyramidal neuron pairs. In contrast, enhancing the sAHP by intracellular dialysis with KMeSO4 reduced burst frequency. Block of GABAA–B inhibitions did not modify the abnormal activity. We describe novel cellular mechanisms where 1) the inhibition of the mAHP plays an essential role in the genesis and regulation of the bursting activity by reducing negative feedback, 2) the sAHP sets the interburst interval by decreasing excitability, and 3) bursting was synchronized by excitatory synaptic interactions that increased in advance and during bursts and decreased throughout the subsequent sAHP. These cellular mechanisms are active in the CA3 region, where epileptiform activity is initiated, and cooperatively regulate the timing of the synchronized rhythmic interictal-like network activity.

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Role of Potassium and Calcium in the Generation of Cellular Bursts in the Dentate Gyrus

Journal of Neurophysiology ◽

10.1152/jn.1997.77.5.2293 ◽

1997 ◽

Vol 77 (5) ◽

pp. 2293-2299 ◽

Cited By ~ 20

Author(s):

Enhui Pan ◽

Janet L. Stringer

Keyword(s):

Dentate Gyrus ◽

Granule Cells ◽

Seizure Activity ◽

Epileptiform Activity ◽

Hippocampal Slices ◽

Extracellular Potassium ◽

Sprague Dawley

Pan, Enhui and Janet L. Stringer. Role of potassium and calcium in the generation of cellular bursts in the dentate gyrus. J. Neurophysiol. 77: 2293–2299, 1997. Epileptiform activity, which appears to be endogenous, has been recorded in the granule cells of the dentate gyrus before the onset of synchronized seizure activity and has been termed cellular bursts. It has been postulated that an increase in input to the dentate gyrus causes a local increase in extracellular K+ concentration ([K+]o) and a decrease in [Ca2+]o that results in this cellular bursting. The first test of this hypothesis is to determine whether the cellular bursts appear in ionic conditions that occur in vivo before the onset of synchronized epileptic activity. This hypothesis was tested in vitro by varying the ionic concentrations in the perfusing solution and recording changes in the granule cells of the dentate gyrus. Intra- and extracellular recordings were made in the dentate gyri of hippocampal slices prepared from anesthetized adult Sprague-Dawley rats. Increasing the extracellular potassium or decreasing the extracellular calcium of the perfusing solution caused three forms of spontaneous activity to appear: depolarizing potentials, action potentials, and cellular bursts. Increasing potassium or decreasing calcium also caused the granule cells to depolarize and reduced their input resistance. No synchronized extracellular field activity was detected. Simultaneously increasing potassium and decreasing calcium caused cellular bursts to appear at concentrations recorded in vivo before the onset of synchronized reverberatory seizure activity.

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Antiepileptic effects of quinine in the pentylenetetrazole model of seizure

European Psychiatry ◽

10.1016/s0924-9338(11)72991-1 ◽

2011 ◽

Vol 26 (S2) ◽

pp. 1286-1286

Author(s):

B. Torabinejad ◽

M. Nassiri-Asl ◽

F. Zamansoltani

Keyword(s):

Neuronal Excitability ◽

Epileptiform Activity ◽

Tween 80 ◽

Clonic Seizure ◽

Positive Control ◽

The Body ◽

Control Group ◽

Gap Junction Channels ◽

Connexin 36

IntroductionQuinine, is an anti-malarial drug that specifically blocks connexin 36 at gap junction channels.ObjectiveQuinine has suppressed ictal epileptiform activity in vitro without decreasing neuronal excitability.AimWe considered the possible anticonvulsant effects of quinine in the pentylenetetrazole (PTZ) model of seizure.MethodsIn five groups, the mice were given quinine at the doses of 20, 30, 40, 50, or 60 mg/kg 30 min before the administration of PTZ (90 mg/kg). Two groups were injected with diazepam, the positive control (0.5, 1 mg/kg) and one group, the control group, was injected with saline + Tween 80 before the administration of PTZ. The onset of a general clonus was used as the endpoint. The general clonus was characterized by forelimb clonus followed by full clonus of the body.ResultsIn the PTZ model, quinine at the dose of 60 mg/kg increased the latency of seizure. However, quinine at 40-60 mg/kg decreased the duration of seizure, dose dependently.ConclusionThe present study provides evidence for anticonvulsant activity of quinine in the generalized clonic seizure of PTZ model. As a result of these finding, we suggest that gap junctions represent an appropriate target for the development of drugs aimed at decreasing epileptiform synchronization and preventing epileptogenesis.

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