Temporal lobe epileptiform activity following systemic administration of 4‐aminopyridine in rats

Lévesque, Maxime; Salami, Pariya; Behr, Charles; Avoli, Massimo

doi:10.1111/epi.12041

Cited by 48 publications

(36 citation statements)

References 51 publications

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“…As observed previously in superfused slices and after in vivo i.p. injection (40,41), epileptiform activity started within 30 min from drug application. Fig.…”

Section: Significancementioning

confidence: 99%

Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo

Sato

Artoni

Landi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

132

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Intracellular chloride ([Cl−] i ) and pH (pH i ) are fundamental regulators of neuronal excitability. They exert wide-ranging effects on synaptic signaling and plasticity and on development and disorders of the brain. The ideal technique to elucidate the underlying ionic mechanisms is quantitative and combined two-photon imaging of [Cl − ] i and pH i , but this has never been performed at the cellular level in vivo. Here, by using a genetically encoded fluorescent sensor that includes a spectroscopic reference (an element insensitive to Cl − and pH), we show that ratiometric imaging is strongly affected by the optical properties of the brain. We have designed a method that fully corrects for this source of error. Parallel measurements of [Cl − ] i and pH i at the single-cell level in the mouse cortex showed the in vivo presence of the widely discussed developmental fall in [Cl − ] i and the role of the K-Cl cotransporter KCC2 in this process. Then, we introduce a dynamic twophoton excitation protocol to simultaneously determine the changes of pH i and [Cl − ] i in response to hypercapnia and seizure activity.I ntracellular ion concentrations are controlled by plasmalemmal transporters and channels, which generate and dissipate ionic electrochemical gradients, respectively (1). In recent years, regulation of the intracellular Cl − concentration ([Cl − ] i ) in neurons has attracted lots of attention, because it is the main ion that carries current across GABA A (and also, glycine) receptors. Changes in [Cl − ] i exert an immediate effect on the reversal potential of GABAergic currents (E GABA ) and, thereby, on the properties of GABA A receptor-mediated transmission (2-4). The "ionic plasticity" of GABAergic signaling involves not only the passive flux of Cl − ions through membrane channels but also, a number of ion transporters that regulate [Cl − ] i . Furthermore, this mechanism is under the control of intracellular signaling cascades that regulate the expression patterns as well as functional properties of ion transporters and channels (5, 6). With regard to long-term ionic modulation of GABAergic transmission, a case in point is the decrease in [Cl − ] i that is generally thought to take place during maturation of most central neurons. According to this widely accepted scenario, the Na-K-2Cl cotransporter NKCC1 accumulates Cl − in immature neurons, thereby promoting depolarizing GABA responses (3, 7-9), which is followed by developmental upregulation of the neuron-specific K-Cl cotransporter KCC2 that is required for the generation of classical hyperpolarizing inhibitory postsynaptic potentials (IPSPs) (10).A wealth of electrophysiological evidence dating back to the work in vivo by Eccles and coworkers (11) has provided evidence for active regulation of [Cl − ] i in mammalian central neurons and its crucial effect on the driving force of Cl − in inhibitory synapses (1). However, thus far, there are no direct data on neuronal [Cl − ] i measured in vivo at the single-cell level in the living brain, and for in...

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“…As observed previously in superfused slices and after in vivo i.p. injection (40,41), epileptiform activity started within 30 min from drug application. Fig.…”

Section: Significancementioning

confidence: 99%

Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo

Sato

Artoni

Landi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

132

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“…Both low-voltage fast activity and hypersynchronous seizure-onset patterns are typically observed in animal models of mesial TLE (Engel et al 1990;Bragin et al 1999;Levesque et al 2012) and in models of acute temporal seizures (Bragin et al 1999;Zhang et al 2012;Levesque et al 2013;Boido et al 2014a). These two patterns may be the expression of the activation of the same networks, because the large-amplitude spikes typically detected in the hypersynchronous pattern are often followed by short runs of low-voltage fast activity (Perucca et al 2014).…”

Section: Seizure Onsetmentioning

confidence: 99%

Initiation, Propagation, and Termination of Partial (Focal) Seizures

Curtis

Avoli

2015

Cold Spring Harb Perspect Med

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The neurophysiological patterns that correlate with partial (focal) seizures are well defined in humans by standard electroencephalogram (EEG) and presurgical depth electrode recordings. Seizure patterns with similar features are reproduced in animal models of partial seizures and epilepsy. However, the network determinants that support interictal spikes, as well as the initiation, progression, and termination of seizures, are still elusive. Recent findings show that inhibitory networks are prominently involved at the onset of these seizures, and that extracellular changes in potassium contribute to initiate and sustain seizure progression. The end of a partial seizure correlates with an increase in network synchronization, which possibly involves both excitatory and inhibitory mechanisms.

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“…11 In addition, systemic injection of 4AP in vivo has been shown to induce LVF onset pattern seizures. 12,13 Finally, we have found that optogenetic activation of parvalbumin (PV)-positive interneurons of entorhinal cortex (EC) in a constitutive model of channelrhodopsin-2 (ChR2) expression leads to the initiation of in vitro LVF seizures in the limbic system. 14 Therefore, in this study, we aimed to test the hypothesis that distinct (ie, LVF and HYP) patterns of seizure onset rely on the activity of different neuronal networks in the in vitro 4AP model using the optogenetic control of PV-positive and somatostatin (SOM)-positive interneurons as well as of calmodulin-dependent protein kinase (CamKII)-positive principal cells in the EC of mice where an enhanced ChR2 opsin was transcranially, locally injected.…”

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confidence: 99%

Activation of specific neuronal networks leads to different seizure onset types

Shiri

Manseau

Lévesque

et al. 2016

Annals of Neurology

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100

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Objective-Ictal events occurring in temporal lobe epilepsy patients and in experimental models mimicking this neurological disorder can be classified, based on their onset pattern, into lowvoltage, fast versus hypersynchronous onset seizures. It has been suggested that the low-voltage, fast onset pattern is mainly contributed by interneuronal (γ-aminobutyric acidergic) signaling, whereas the hypersynchronous onset involves the activation of principal (glutamatergic) cells.Methods-Here, we tested this hypothesis using the optogenetic control of parvalbumin-positive or somatostatin-positive interneurons and of calmodulin-dependent, protein kinase-positive, principal cells in the mouse entorhinal cortex in the in vitro 4-aminopyridine model of epileptiform synchronization.Results-We found that during 4-aminopyridine application, both spontaneous seizure-like events and those induced by optogenetic activation of interneurons displayed low-voltage, fast onset patterns that were associated with a higher occurrence of ripples than of fast ripples. In contrast, seizures induced by the optogenetic activation of principal cells had a hypersynchronous onset pattern with fast ripple rates that were higher than those of ripples.Interpretation-Our results firmly establish that under a similar experimental condition (ie, bath application of 4-aminopyridine), the initiation of low-voltage, fast and of hypersynchronous onset seizures in the entorhinal cortex depends on the preponderant involvement of interneuronal and principal cell networks, respectively.Seizures in patients presenting with temporal lobe epilepsy (TLE) are mainly characterized by 2 distinct electrographic onset patterns, defined as low-voltage, fast (LVF) and hypersynchronous (HYP). 1,2 LVF seizures are characterized at onset by the occurrence of a sentinel spike followed by low-amplitude, high-frequency activity, whereas the initiation of Recently, the analysis of high-frequency oscillations (HFOs; ripples: 80-200Hz, fast ripples: 250-500Hz) during spontaneous HYP and LVF seizures in the pilocarpine and kainic acid model of TLE has suggested that these 2 seizure onset patterns may rely on distinct mechanisms of initiation. LVF seizures were found to be mainly associated with HFOs in the ripple frequency range, thus suggesting the predominant involvement of interneuronal (inhibitory) networks; in contrast, HYP seizures were mostly accompanied by fast ripple occurrence, thus highlighting the potential role of principal (glutamatergic) networks. 6,7 Evidence obtained to date suggests that pathologic HFOs in the ripple band should represent population inhibitory postsynaptic potentials generated by principal neurons entrained by synchronously active interneuron networks, whereas those in the fast ripple band reflect the synchronous firing of abnormally active principal cells, and thus are not dependent on inhibitory processes. [8][9][10] It has been demonstrated that 4-aminopyridine (4AP) application induces LVF onset discharges in several limbic and para...

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Temporal lobe epileptiform activity following systemic administration of 4‐aminopyridine in rats

Cited by 48 publications

References 51 publications

Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo

Simultaneous two-photon imaging of intracellular chloride concentration and pH in mouse pyramidal neurons in vivo

Initiation, Propagation, and Termination of Partial (Focal) Seizures

Activation of specific neuronal networks leads to different seizure onset types

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