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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.

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Hot-spots of activity are associated with weak topological                            connectivity.A Raster plots showing the response of model neuronal                            network to the localized lesion of gap junction connectivity. The extent                            of lesion is parameterized by the probability                                     to destroy                            a connection between a pair of model neurons in the predefined area                                    . The                            timing of lesion is marked with red line. Top panel:                                    . Middle                            panel: . Bottom                            panel: . Other                            parameters are: .                                B Averaged firing rate                                    (meanS.E.M.) in                            the lesioned subnetwork vs. the size of the lesioned subnetwork. Closed                            squares: . Open                            squares: . In all                            cases . Firing rate was computed over the time window                            of 20 seconds. C Averaged firing rate                                    (meanS.E.M.) in                            the intact subnetwork, vs. the size of the lesioned subnetwork. Closed                            squares: . Open                            squares: . In all                            cases . For comparison, dashed line is the averaged                            neuronal firing rate in baseline conditions (model network with fully                            intact connectivity). Firing rate was computed over the time window of                            20 seconds. D Raster plot showing the response of a model                            network with electrical and chemical synapses to the localized breach in                            gap junction connectivity. Disruption to gap junction connectivity was                            applied at time T = 2 seconds and is marked with                            red line. Chemical synaptic connections were added to the model as                            described in Methods.
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pone-0020572-g004: Hot-spots of activity are associated with weak topological connectivity.A Raster plots showing the response of model neuronal network to the localized lesion of gap junction connectivity. The extent of lesion is parameterized by the probability to destroy a connection between a pair of model neurons in the predefined area . The timing of lesion is marked with red line. Top panel: . Middle panel: . Bottom panel: . Other parameters are: . B Averaged firing rate (meanS.E.M.) in the lesioned subnetwork vs. the size of the lesioned subnetwork. Closed squares: . Open squares: . In all cases . Firing rate was computed over the time window of 20 seconds. C Averaged firing rate (meanS.E.M.) in the intact subnetwork, vs. the size of the lesioned subnetwork. Closed squares: . Open squares: . In all cases . For comparison, dashed line is the averaged neuronal firing rate in baseline conditions (model network with fully intact connectivity). Firing rate was computed over the time window of 20 seconds. D Raster plot showing the response of a model network with electrical and chemical synapses to the localized breach in gap junction connectivity. Disruption to gap junction connectivity was applied at time T = 2 seconds and is marked with red line. Chemical synaptic connections were added to the model as described in Methods.

Mentions: As Figure 4 shows, lesioning of gap junction connectivity at time T = 6 seconds led to increase in spiking activity for model neurons in the traumatized subnetwork. In Figure 4A, the time at which the connectivity was lesioned and the extent of lesioned region are marked with red line. Firing rate of model neurons in the traumatized subnetwork was higher for larger lesions (higher values of in Figure 4B) and increased for stronger disruption of gap junction connectivity inside the traumatized region (higher value of plesion in Figure 4B). Interestingly, the firing rate of the neurons with intact connectivity also increased (Figure 4C), which was largely attributed to increase of activity of neurons near the border with traumatized region, but propagation of high frequency activity through the intact network was not supported (Figure 4A bottom panel). Overall, following the lesion, the firing rate of lesioned neurons could increase up to 10-fold as compared with the activity in the baseline model before lesion (Figure 4B,C). Thus, localized lesions of gap junction connectivity can create localized hot-spots of intense activity.


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

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

Hot-spots of activity are associated with weak topological                            connectivity.A Raster plots showing the response of model neuronal                            network to the localized lesion of gap junction connectivity. The extent                            of lesion is parameterized by the probability                                     to destroy                            a connection between a pair of model neurons in the predefined area                                    . The                            timing of lesion is marked with red line. Top panel:                                    . Middle                            panel: . Bottom                            panel: . Other                            parameters are: .                                B Averaged firing rate                                    (meanS.E.M.) in                            the lesioned subnetwork vs. the size of the lesioned subnetwork. Closed                            squares: . Open                            squares: . In all                            cases . Firing rate was computed over the time window                            of 20 seconds. C Averaged firing rate                                    (meanS.E.M.) in                            the intact subnetwork, vs. the size of the lesioned subnetwork. Closed                            squares: . Open                            squares: . In all                            cases . For comparison, dashed line is the averaged                            neuronal firing rate in baseline conditions (model network with fully                            intact connectivity). Firing rate was computed over the time window of                            20 seconds. D Raster plot showing the response of a model                            network with electrical and chemical synapses to the localized breach in                            gap junction connectivity. Disruption to gap junction connectivity was                            applied at time T = 2 seconds and is marked with                            red line. Chemical synaptic connections were added to the model as                            described in Methods.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105095&req=5

pone-0020572-g004: Hot-spots of activity are associated with weak topological connectivity.A Raster plots showing the response of model neuronal network to the localized lesion of gap junction connectivity. The extent of lesion is parameterized by the probability to destroy a connection between a pair of model neurons in the predefined area . The timing of lesion is marked with red line. Top panel: . Middle panel: . Bottom panel: . Other parameters are: . B Averaged firing rate (meanS.E.M.) in the lesioned subnetwork vs. the size of the lesioned subnetwork. Closed squares: . Open squares: . In all cases . Firing rate was computed over the time window of 20 seconds. C Averaged firing rate (meanS.E.M.) in the intact subnetwork, vs. the size of the lesioned subnetwork. Closed squares: . Open squares: . In all cases . For comparison, dashed line is the averaged neuronal firing rate in baseline conditions (model network with fully intact connectivity). Firing rate was computed over the time window of 20 seconds. D Raster plot showing the response of a model network with electrical and chemical synapses to the localized breach in gap junction connectivity. Disruption to gap junction connectivity was applied at time T = 2 seconds and is marked with red line. Chemical synaptic connections were added to the model as described in Methods.
Mentions: As Figure 4 shows, lesioning of gap junction connectivity at time T = 6 seconds led to increase in spiking activity for model neurons in the traumatized subnetwork. In Figure 4A, the time at which the connectivity was lesioned and the extent of lesioned region are marked with red line. Firing rate of model neurons in the traumatized subnetwork was higher for larger lesions (higher values of in Figure 4B) and increased for stronger disruption of gap junction connectivity inside the traumatized region (higher value of plesion in Figure 4B). Interestingly, the firing rate of the neurons with intact connectivity also increased (Figure 4C), which was largely attributed to increase of activity of neurons near the border with traumatized region, but propagation of high frequency activity through the intact network was not supported (Figure 4A bottom panel). Overall, following the lesion, the firing rate of lesioned neurons could increase up to 10-fold as compared with the activity in the baseline model before lesion (Figure 4B,C). Thus, localized lesions of gap junction connectivity can create localized hot-spots of intense activity.

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