Dataset Information

Activity-induced spontaneous spikes in GABAergic neurons suppress seizure discharges: an implication of computational modeling.

ABSTRACT:

Background

Epilepsy, a prevalent neurological disorder, appears self-termination. The endogenous mechanism for seizure self-termination remains to be addressed in order to develop new strategies for epilepsy treatment. We aim to examine the role of activity-induced spontaneous spikes at GABAergic neurons as an endogenous mechanism in the seizure self-termination.

Methods and results

Neuronal spikes were induced by depolarization pulses at cortical GABAergic neurons from temporal lobe epilepsy patients and mice, in which some of these neurons fired activity-induced spontaneous spikes. Neural networks including excitatory and inhibitory neurons were computationally constructed, and their functional properties were based on our studies from whole-cell recordings. With the changes in the portion and excitability of inhibitory neurons that generated activity-induced spontaneous spike, the efficacies to suppress synchronous seizure activity were analyzed, such as its onset time, decay slope and spike frequency. The increases in the proportion and excitability of inhibitory neurons that generated activity-induced spontaneous spikes effectively suppressed seizure activity in neural networks. These factors synergistically strengthened the efficacy of seizure activity suppression.

Conclusion

Our study supports a notion that activity-induced spontaneous spikes in GABAergic neurons may be an endogenous mechanism for seizure self-termination. A potential therapeutic strategy for epilepsy is to upregulate the cortical inhibitory neurons that generate activity-induced spontaneous spikes.

SUBMITTER: Lu W

PROVIDER: S-EPMC5464796 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Publications

Activity-induced spontaneous spikes in GABAergic neurons suppress seizure discharges: an implication of computational modeling.

Lu Wei W Feng Jing J Wen Bo B Wang Kewei K Wang Jin-Hui JH

Oncotarget 20170501 20

<h4>Background</h4>Epilepsy, a prevalent neurological disorder, appears self-termination. The endogenous mechanism for seizure self-termination remains to be addressed in order to develop new strategies for epilepsy treatment. We aim to examine the role of activity-induced spontaneous spikes at GABAergic neurons as an endogenous mechanism in the seizure self-termination.<h4>Methods and results</h4>Neuronal spikes were induced by depolarization pulses at cortical GABAergic neurons from temporal l ...[more]

PMID: 28427143

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Project description:Epileptic seizure dynamics span multiple scales in space and time. Understanding seizure mechanisms requires identifying the relations between seizure components within and across these scales, together with the analysis of their dynamical repertoire. Mathematical models have been developed to reproduce seizure dynamics across scales ranging from the single neuron to the neural population. In this study, we develop a network model of spiking neurons and systematically investigate the conditions, under which the network displays the emergent dynamic behaviors known from the Epileptor, which is a well-investigated abstract model of epileptic neural activity. This approach allows us to study the biophysical parameters and variables leading to epileptiform discharges at cellular and network levels. Our network model is composed of two neuronal populations, characterized by fast excitatory bursting neurons and regular spiking inhibitory neurons, embedded in a common extracellular environment represented by a slow variable. By systematically analyzing the parameter landscape offered by the simulation framework, we reproduce typical sequences of neural activity observed during status epilepticus. We find that exogenous fluctuations from extracellular environment and electro-tonic couplings play a major role in the progression of the seizure, which supports previous studies and further validates our model. We also investigate the influence of chemical synaptic coupling in the generation of spontaneous seizure-like events. Our results argue towards a temporal shift of typical spike waves with fast discharges as synaptic strengths are varied. We demonstrate that spike waves, including interictal spikes, are generated primarily by inhibitory neurons, whereas fast discharges during the wave part are due to excitatory neurons. Simulated traces are compared with in vivo experimental data from rodents at different stages of the disorder. We draw the conclusion that slow variations of global excitability, due to exogenous fluctuations from extracellular environment, and gap junction communication push the system into paroxysmal regimes. We discuss potential mechanisms underlying such machinery and the relevance of our approach, supporting previous detailed modeling studies and reflecting on the limitations of our methodology.

Project description:In organotypic hippocampal slice cultures, principal neurons form aberrant excitatory connections with other principal cells in response to slicing induced deafferentation, similar to mechanisms underlying epileptogenesis in posttraumatic epilepsy. To investigate the consequences of this synaptogenesis, the authors recorded field-potential activity from area CA3 during perfusion with the complete growth medium used during incubation. At 7 days in vitro, slice cultures only displayed multiunit activity. At 14 days in vitro, the majority displayed population bursts reminiscent of interictal-like spikes, but sustained synchronous activity was rare. Band-pass filtering of interictal discharges revealed fast ripple-like complexes, similar to in vivo recordings. Spontaneous ictal-like activity became progressively more prevalent with age: at 21 days in vitro, 50% of organotypic hippocampal slice cultures displayed long-lasting, ictal-like discharges that could be suppressed by phenytoin, whereas interictal activity was not suppressed. The fraction of cultures displaying ictal events continually increased with incubation time. Quantification of population spike activity throughout epileptogenesis using automatic detection and clustering algorithms confirmed the appearance of interictal-like activity before ictal-like discharges and also revealed high-frequency pathologic multiunit activity in slice cultures at 14 to 17 days in vitro. These experiments indicate that interictal-like spikes precede the appearance of ictal-like activity in a reduced in vitro preparation. Epileptiform activity in cultures resembled in vivo epilepsy, including sensitivity to anticonvulsants and steadily increasing seizure incidence over time, although seizure frequency and rate of epileptogenesis were higher in vitro. Organotypic hippocampal slice cultures comprise a useful model system for investigating mechanisms of epileptogenesis as well as developing antiepileptic and antiepileptogenic drugs.

Dataset Information

Activity-induced spontaneous spikes in GABAergic neurons suppress seizure discharges: an implication of computational modeling.

Background

Methods and results

Conclusion

Publications

Activity-induced spontaneous spikes in GABAergic neurons suppress seizure discharges: an implication of computational modeling.

Similar Datasets

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