Role of CA3 theta-modulated interneurons during the transition to spontaneous seizures

Karunakaran, Suganya; Grasse, Dane W.; Moxon, Karen A.

doi:10.1016/j.expneurol.2016.06.027

Cited by 31 publications

(23 citation statements)

References 77 publications

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“…This hypothesis is in line with studies showing that the application of the GABA A receptor antagonist bicuculline favors the appearance of fast ripples and widens the size of their generating area, suggesting that cell populations generating fast ripples are under the control of surrounding inhibitory networks. 50 48 We have also shown that seizures occur more frequently during the optogenetic activation of hippocampal PV-positive interneurons; though surprising, this finding is line with previous evidence obtained in vitro in the 4AP model.…”

Section: Discussionsupporting

confidence: 91%

“…44,45 A decrease in fast ripple occurrence in PV-ChR2 animals could therefore be caused by the emergence of a strong inhibitory action on hippocampal networks generating pathological network activity, due to the optogenetic activation of PV-positive GABAergic inhibitory interneurons. 24,50 It is, however, unclear whether θ activity before seizures favors ictogenesis or reflects a compensatory mechanism developed to prevent seizure initiation. 46,47 This hypothesis is further supported by the fact that in our study, optogenetic activation of PV-positive interneurons induced significantly higher rates of isolated ripples in PV-ChR2 animals, which are believed to reflect population inhibitory postsynaptic potentials generated by principal neurons entrained by synchronously active interneuron networks.…”

Section: Discussionmentioning

confidence: 99%

“…Excessive activation of GABA A receptors was triggered in our study by stimulation at θ frequency, which is in line with previous studies in which it was reported that an increase in θ rhythms occurs before seizures in 4AP-and pilocarpine-treated animals. 24,50 It is, however, unclear whether θ activity before seizures favors ictogenesis or reflects a compensatory mechanism developed to prevent seizure initiation. 50…”

Section: Discussionmentioning

confidence: 99%

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Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Lévesque

Chen

Etter

et al. 2019

Annals of Neurology

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Objective: To establish the effects induced by long-term, unilateral stimulation of parvalbumin (PV)-positive interneurons on seizures, interictal spikes, and high-frequency oscillations (80-500Hz) occurring after pilocarpine-induced status epilepticus (SE)-a proven model of mesial temporal lobe epilepsy (MTLE)-in transgenic mice expressing or not expressing ChR2. Methods: PV-ChR2 (n = 6) and PV-Cre (n = 6) mice were treated with pilocarpine to induce SE. Three hours after SE onset, unilateral optogenetic stimulation (450nm, 25mW, 20-millisecond pulses delivered at 8Hz for 30 seconds every 2 minutes) of CA3 PV-positive interneurons was implemented for 14 continuous days in both groups. Results: Rates of seizures (p < 0.01), interictal spikes (p < 0.001), and interictal spikes with fast ripples (250-500Hz) (p < 0.001) were lower in PV-ChR2 than in PV-Cre mice. Ripples (80-200Hz) occurring outside of interictal spikes had higher rates in the PV-ChR2 group (p < 0.01), whereas isolated fast ripples had lower rates (p < 0.01). However, seizure probability was higher during optogenetic stimulation in PV-ChR2 compared to PV-Cre animals (p < 0.05). Interpretation: Our findings show that the unilateral activation of CA3 PV-positive interneurons exerts anti-ictogenic effects associated with decreased rates of interictal spikes and fast ripples in this MTLE model. However, PV-positive interneuron stimulation can paradoxically trigger seizures in epileptic animals, supporting the notion that γ-aminobutyric acid type A signaling can also initiate ictogenesis. ANN NEUROL 2019;86:714-728 View this article online at wileyonlinelibrary.com.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Paradoxical effects of optogenetic stimulation in mesial temporal lobe epilepsy

Lévesque

Chen

Etter

et al. 2019

Annals of Neurology

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“…Changes in theta and theta-field coherence have been identified in animal models of epilepsy, 18,20,42,43 but this is the first demonstration of such coherence in human epilepsy. This result suggests that the synaptic barrages from the cortex are likely to be part of a selective, feed-forward inhibitory network.…”

Section: Regional Synchrony Entrains Inhibition In Mtlmentioning

confidence: 85%

Increased neuronal synchrony prepares mesial temporal networks for seizures of neocortical origin

et al. 2018

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Summary Objective To gain understanding of the neuronal mechanisms underlying regional seizure spread, the impact of regional synchrony between seizure focus and downstream networks on neuronal activity during the transition to seizure in those downstream networks was assessed. Methods Seven patients undergoing diagnostic intracranial electroencephalographic studies for surgical resection of epileptogenic regions were implanted with subdural clinical electrodes into the cortex (site of seizure initiation) and mesial temporal lobe (MTL) structures (downstream) as well as microwires into MTL. Neural activity was recorded (24/7) in parallel with the clinical intracranial electroencephalogram recordings for the duration of the patient's diagnostic stay. Changes in (1) regional synchrony (ie, coherence) between the presumptive neocortical seizure focus and MTL, (2) local synchrony between MTL neurons and their local field potential, and (3) neuronal firing rates within MTL in the time leading up to seizure were examined to study the mechanisms underlying seizure spread. Results In seizures of neocortical origin, an increase in regional synchrony preceded the spread of seizures into MTL (predominantly hippocampal). Within frequencies similar to those of regional synchrony, MTL networks showed an increase in unit‐field coherence and a decrease in neuronal firing rate, specifically for inhibitory interneuron populations but not pyramidal cell populations. Significance These results suggest a mechanism of spreading seizures whereby the seizure focus first synchronizes local field potentials in downstream networks to the seizure activity. This change in local field coherence modifies the activity of interneuron populations in these downstream networks, which leads to the attenuation of interneuronal firing rate, effectively shutting down local interneuron populations prior to the spread of seizure. Therefore, regional synchrony may influence the failure of downstream interneurons to prevent the spread of the seizures during generalization.

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“…Singleunit recordings obtained in vivo from the hippocampus of these epileptic animals have shown that seizure onset correlates with an arrest of principal neuron firing along with increased interneuron discharge. [18][19][20][21][22][23] Because the specific imbalance between excitation and inhibition at LVF onset has only been observed in pharmacological and optogenetic models, the relevance to spontaneous LVF seizure genesis in humans with epilepsy remains unclear. Limited prior in vivo extracellular recordings of action potentials during spontaneous seizures with LVF onset in humans have demonstrated both highly heterogeneous ensemble activity 24,25 and suppressed firing followed by a slowly propagating wave of increased neuronal firing.…”

mentioning

confidence: 99%