Reduced ictogenic potential of 4-aminopyridine in the hippocampal region in the pilocarpine model of epilepsy

Zahn, R.; Liotta, Agustin; Kim, Simon; Sandow, Nora; Heinemann, Uwe

doi:10.1016/j.neulet.2012.01.071

Cited by 8 publications

(10 citation statements)

References 25 publications

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“…The frequency of ictal discharges was comparable between the two types of tissue; however, only 13 out of 17 epileptic slices (72%) generated ictal activity and these events were shorter in duration (p < 0.05). The reduced ictogenic potential of 4AP in models of chronic epilepsy has been previously reported for the medial EC (Zahn et al, 2008(Zahn et al, , 2012. Here, we identified a similar effect in the PC since we recorded fewer interictal discharges as well as shorter ictal discharges (Fig.…”

Section: Ap-induced Epileptiform Activity In Nec and Epileptic Tissuesupporting

confidence: 88%

“…In our present experiments as well, we observed seizure-like events in all EC and in 72% of PC recordings from epileptic slices using the same concentration of 4AP. The absence of ictal activity in 28% of PC recordings may mirror the SE-induced changes that, as suggested by Zahn et al (2012), should alter the expression of 4AP-sensitive potassium channels. Therefore, the only difference is that we recorded fewer but longer interictal discharges and shorter ictal events in PC as well as fewer interictal and ictal discharges with shorter durations in the EC in comparison to control slices.…”

Section: Ap-induced Epileptiform Discharges In Control and Epilepticmentioning

confidence: 89%

“…It has been reported that brain slices obtained from epileptic rats are characterized by a reduced ability to generate ictal discharges in vitro during 4AP treatment when recordings are performed in the medial EC (Zahn et al, 2012). They showed that 50 μM 4AP could induce seizure-like events in the medial EC in only 20% of pilocarpine-treated slices.…”

Section: Ap-induced Epileptiform Discharges In Control and Epilepticmentioning

confidence: 99%

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Neurosteroidal modulation of in vitro epileptiform activity is enhanced in pilocarpine-treated epileptic rats

Shiri

Herrington

Lévesque

2015

Neurobiology of Disease

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We employed field potential recordings in brain slices obtained from pilocarpine-treated epileptic (4-5 weeks following a pilocarpine-induced status epilepticus) and age-matched, non-epileptic control (NEC) rats to establish the effects of the neurosteroid allotetrahydrodeoxycorticosterone (THDOC) on the epileptiform activity -including high frequency oscillations (HFOs; ripples: 80-200 Hz, fast ripples: 250-500 Hz) -induced by 4-aminopyridine (4AP) in piriform (PC) and entorhinal (EC) cortices. Both structures are highly susceptible to generate seizures and may also be involved in epileptogenesis. We found that THDOC application to pilocarpine-treated slices: (i) decreased interictal discharge frequency in PC while increasing it in EC; (ii) abolished ictal discharges in both areas in approx. one third of the experiments and reduced them in frequency and duration in the remaining experiments; and (iii) increased the occurrence of ripples and fast ripples associated to interictal events, and modified their pattern of occurrence during ictal discharges in both PC and EC. These effects were either weaker or absent in NEC tissue. Our results demonstrate that THDOC plays a structure-dependent modulatory role in epileptiform synchronization in the pilocarpine-treated epileptic rat brain where its actions are more pronounced than in NEC tissue. This evidence supports the application of neurosteroids as potential antiepileptic tools.

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Section: Ap-induced Epileptiform Activity In Nec and Epileptic Tissuesupporting

confidence: 88%

Section: Ap-induced Epileptiform Discharges In Control and Epilepticmentioning

confidence: 89%

Section: Ap-induced Epileptiform Discharges In Control and Epilepticmentioning

confidence: 99%

See 1 more Smart Citation

Neurosteroidal modulation of in vitro epileptiform activity is enhanced in pilocarpine-treated epileptic rats

Shiri

Herrington

Lévesque

2015

Neurobiology of Disease

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“…1987; Perreault & Avoli, 1989, 1991; but see Streit et al . 2011; Zahn et al . 2012) and 0.5 m m Mg 2+ , a local NMDA stimulation evokes a focal ictal discharge (mean duration, 32.9 ± 0.2 s, n = 89; Fig.…”

Section: Resultsmentioning

confidence: 99%

Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy

Cammarota

Losi

Chiavegato

et al. 2013

The Journal of Physiology

159

163

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Key points In focal epilepsy the propagation of seizure discharges arising at restricted brain sites is opposed by feedforward inhibition. Failure of this inhibition marks focal seizure propagation to distant neurons. The cellular source of inhibition and the mechanism of inhibition failure are, however, undefined. Here we reveal that a subclass of GABAergic interneurons, i.e. the parvalbumin‐expressing, fast‐spiking interneurons, are a main source of the inhibitory signal that locally restrains seizures. Furthermore, a firing impairment in these interneurons, probably due to a drastic membrane depolarization, is an important event that by reducing the overall strength of local inhibition allows seizures to propagate across the cortex. Our data suggest that modulation of fast‐spiking interneuron activity may represent a new therapeutic strategy to prevent generalization of focal epilepsies. Abstract In different animal models of focal epilepsy, seizure‐like ictal discharge propagation is transiently opposed by feedforward inhibition. The specific cellular source of this signal and the mechanism by which inhibition ultimately becomes ineffective are, however, undefined. We used a brain slice model to study how focal ictal discharges that were repetitively evoked from the same site, and at precise times, propagate across the cortex. We used Ca2+ imaging and simultaneous single/dual cell recordings from pyramidal neurons (PyNs) and different classes of interneurons in rodents, including G42 and GIN transgenic mice expressing the green fluorescence protein in parvalbumin (Pv)‐fast spiking (FS) and somatostatin (Som) interneurons, respectively. We found that these two classes of interneurons fired intensively shortly after ictal discharge generation at the focus. The inhibitory barrages that were recorded in PyNs occurred in coincidence with Pv‐FS, but not with Som interneuron burst discharges. Furthermore, the strength of inhibitory barrages increased or decreased in parallel with increased or decreased firing in Pv‐FS interneurons but not in Som interneurons. A firing impairment of Pv‐FS interneurons caused by a membrane depolarization was found to precede ictal discharge onset in neighbouring pyramidal neurons. This event may account for the collapse of local inhibition that allows spatially defined clusters of PyNs to be recruited into propagating ictal discharges. Our study demonstrates that Pv‐FS interneurons are a major source of the inhibitory barrages that oppose ictal discharge propagation and raises the possibility that targeting Pv‐FS interneurons represents a new therapeutic strategy to prevent the generalization of human focal seizures.

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“…Slices were pre-incubated for 1 h either with ONX-0914, the b5i-specific inhibitor, or with PR825, the b5-specific inhibitor, both covalently binding the respective proteasome subunits. Then, the medium was removed and replaced by ACSF containing 4-AP for 1 h to evoke SLEs (Zahn et al, 2008;Zahn et al, 2012). Outcome measures were the latency to SLEs onset ( Fig.…”

Section: Electrophysiologymentioning

confidence: 99%

The immunoproteasome β5i subunit is a key contributor to ictogenesis in a rat model of chronic epilepsy

Mishto

Raza

Biase

et al. 2015

Brain, Behavior, and Immunity

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Reduced ictogenic potential of 4-aminopyridine in the hippocampal region in the pilocarpine model of epilepsy

Cited by 8 publications

References 25 publications

Neurosteroidal modulation of in vitro epileptiform activity is enhanced in pilocarpine-treated epileptic rats

Neurosteroidal modulation of in vitro epileptiform activity is enhanced in pilocarpine-treated epileptic rats

Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy

The immunoproteasome β5i subunit is a key contributor to ictogenesis in a rat model of chronic epilepsy

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