Limits...
Gap junctions and epileptic seizures--two sides of the same coin?

Volman V, Perc M, Bazhenov M - PLoS ONE (2011)

Bottom Line: Here we used a computational modeling approach to address the role of neuronal gap junctions in shaping the stability of a network to perturbations that are often associated with the onset of epileptic seizures.This implies that the experimentally observed post-seizure additions of gap junctions could serve to prevent further escalations, suggesting furthermore that they are a consequence of an adaptive response of the neuronal network to the pathological activity.Our results thus reveal a complex role of electrical coupling in relation to epileptiform events.

View Article: PubMed Central - PubMed

Affiliation: Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. volman@salk.edu

ABSTRACT
Electrical synapses (gap junctions) play a pivotal role in the synchronization of neuronal ensembles which also makes them likely agonists of pathological brain activity. Although large body of experimental data and theoretical considerations indicate that coupling neurons by electrical synapses promotes synchronous activity (and thus is potentially epileptogenic), some recent evidence questions the hypothesis of gap junctions being among purely epileptogenic factors. In particular, an expression of inter-neuronal gap junctions is often found to be higher after the experimentally induced seizures than before. Here we used a computational modeling approach to address the role of neuronal gap junctions in shaping the stability of a network to perturbations that are often associated with the onset of epileptic seizures. We show that under some circumstances, the addition of gap junctions can increase the dynamical stability of a network and thus suppress the collective electrical activity associated with seizures. This implies that the experimentally observed post-seizure additions of gap junctions could serve to prevent further escalations, suggesting furthermore that they are a consequence of an adaptive response of the neuronal network to the pathological activity. However, if the seizures are strong and persistent, our model predicts the existence of a critical tipping point after which additional gap junctions no longer suppress but strongly facilitate the escalation of epileptic seizures. Our results thus reveal a complex role of electrical coupling in relation to epileptiform events. Which dynamic scenario (seizure suppression or seizure escalation) is ultimately adopted by the network depends critically on the strength and duration of seizures, in turn emphasizing the importance of temporal and causal aspects when linking gap junctions with epilepsy.

Show MeSH

Related in: MedlinePlus

Increased gap junction connectivity can mitigate the response to mild                            perturbation.A Color panel is the surface plot of firing rate (averaged                            over non-overlapping bins of 100 ms and over all model neurons) vs. the                            probability  to                            establish a new gap junction between a pair of previously unconnected                            neurons from the affected area (,). Color                            code is blue for low firing rate and red for high firing rate.                            Horizontal axis is simulation time ([0–10] seconds).                            Background noise intensity  for the                            set of  model                            neurons was perturbed at  (dashed                            red line through Panels B,C), and progressively increased to achieve                            5-fold higher values at time 10 seconds (scale bar in lowest panel). Gap                            junction connectivity for  model                            neurons was increased (as specified by ) at time                                     (dashed                            blue line through Panels B,C). B Raster plot of                            network's activity for . Other                            parameters: .                                C Third panel: Raster plot of network's activity                            for . Other parameters:                                    .
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3105095&req=5

pone-0020572-g005: Increased gap junction connectivity can mitigate the response to mild perturbation.A Color panel is the surface plot of firing rate (averaged over non-overlapping bins of 100 ms and over all model neurons) vs. the probability to establish a new gap junction between a pair of previously unconnected neurons from the affected area (,). Color code is blue for low firing rate and red for high firing rate. Horizontal axis is simulation time ([0–10] seconds). Background noise intensity for the set of model neurons was perturbed at (dashed red line through Panels B,C), and progressively increased to achieve 5-fold higher values at time 10 seconds (scale bar in lowest panel). Gap junction connectivity for model neurons was increased (as specified by ) at time (dashed blue line through Panels B,C). B Raster plot of network's activity for . Other parameters: . C Third panel: Raster plot of network's activity for . Other parameters: .

Mentions: To address these questions, we considered a simple scenario in which model neurons in the predefined sub-network (square block, total number of perturbed neurons ) were subjected to higher intensities of stimulation current as compared to the baseline input intensity applied to the neurons in the rest of the network. The change of the stimulus intensity was initiated at time (marked with red dashed line in Figure 5), and the intensity of the stimulation was gradually increased (Figure 5, bottom panel). Overall, starting from the time of the initial perturbation, the background current intensity increased 5-fold compared to its baseline value (from to ). To address the possible regulatory effect of gap junction connectivity, at time (marked with blue dashed line in Figure 5, ) new gap junction connections were formed between the model neurons in the perturbed sub-network, such that the probability to create a new gap junction between a pair of previously unconnected neurons was .


Gap junctions and epileptic seizures--two sides of the same coin?

Volman V, Perc M, Bazhenov M - PLoS ONE (2011)

Increased gap junction connectivity can mitigate the response to mild                            perturbation.A Color panel is the surface plot of firing rate (averaged                            over non-overlapping bins of 100 ms and over all model neurons) vs. the                            probability  to                            establish a new gap junction between a pair of previously unconnected                            neurons from the affected area (,). Color                            code is blue for low firing rate and red for high firing rate.                            Horizontal axis is simulation time ([0–10] seconds).                            Background noise intensity  for the                            set of  model                            neurons was perturbed at  (dashed                            red line through Panels B,C), and progressively increased to achieve                            5-fold higher values at time 10 seconds (scale bar in lowest panel). Gap                            junction connectivity for  model                            neurons was increased (as specified by ) at time                                     (dashed                            blue line through Panels B,C). B Raster plot of                            network's activity for . Other                            parameters: .                                C Third panel: Raster plot of network's activity                            for . Other parameters:                                    .
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105095&req=5

pone-0020572-g005: Increased gap junction connectivity can mitigate the response to mild perturbation.A Color panel is the surface plot of firing rate (averaged over non-overlapping bins of 100 ms and over all model neurons) vs. the probability to establish a new gap junction between a pair of previously unconnected neurons from the affected area (,). Color code is blue for low firing rate and red for high firing rate. Horizontal axis is simulation time ([0–10] seconds). Background noise intensity for the set of model neurons was perturbed at (dashed red line through Panels B,C), and progressively increased to achieve 5-fold higher values at time 10 seconds (scale bar in lowest panel). Gap junction connectivity for model neurons was increased (as specified by ) at time (dashed blue line through Panels B,C). B Raster plot of network's activity for . Other parameters: . C Third panel: Raster plot of network's activity for . Other parameters: .
Mentions: To address these questions, we considered a simple scenario in which model neurons in the predefined sub-network (square block, total number of perturbed neurons ) were subjected to higher intensities of stimulation current as compared to the baseline input intensity applied to the neurons in the rest of the network. The change of the stimulus intensity was initiated at time (marked with red dashed line in Figure 5), and the intensity of the stimulation was gradually increased (Figure 5, bottom panel). Overall, starting from the time of the initial perturbation, the background current intensity increased 5-fold compared to its baseline value (from to ). To address the possible regulatory effect of gap junction connectivity, at time (marked with blue dashed line in Figure 5, ) new gap junction connections were formed between the model neurons in the perturbed sub-network, such that the probability to create a new gap junction between a pair of previously unconnected neurons was .

Bottom Line: Here we used a computational modeling approach to address the role of neuronal gap junctions in shaping the stability of a network to perturbations that are often associated with the onset of epileptic seizures.This implies that the experimentally observed post-seizure additions of gap junctions could serve to prevent further escalations, suggesting furthermore that they are a consequence of an adaptive response of the neuronal network to the pathological activity.Our results thus reveal a complex role of electrical coupling in relation to epileptiform events.

View Article: PubMed Central - PubMed

Affiliation: Computational Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California, United States of America. volman@salk.edu

ABSTRACT
Electrical synapses (gap junctions) play a pivotal role in the synchronization of neuronal ensembles which also makes them likely agonists of pathological brain activity. Although large body of experimental data and theoretical considerations indicate that coupling neurons by electrical synapses promotes synchronous activity (and thus is potentially epileptogenic), some recent evidence questions the hypothesis of gap junctions being among purely epileptogenic factors. In particular, an expression of inter-neuronal gap junctions is often found to be higher after the experimentally induced seizures than before. Here we used a computational modeling approach to address the role of neuronal gap junctions in shaping the stability of a network to perturbations that are often associated with the onset of epileptic seizures. We show that under some circumstances, the addition of gap junctions can increase the dynamical stability of a network and thus suppress the collective electrical activity associated with seizures. This implies that the experimentally observed post-seizure additions of gap junctions could serve to prevent further escalations, suggesting furthermore that they are a consequence of an adaptive response of the neuronal network to the pathological activity. However, if the seizures are strong and persistent, our model predicts the existence of a critical tipping point after which additional gap junctions no longer suppress but strongly facilitate the escalation of epileptic seizures. Our results thus reveal a complex role of electrical coupling in relation to epileptiform events. Which dynamic scenario (seizure suppression or seizure escalation) is ultimately adopted by the network depends critically on the strength and duration of seizures, in turn emphasizing the importance of temporal and causal aspects when linking gap junctions with epilepsy.

Show MeSH
Related in: MedlinePlus