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

Schematic presentation of the effect that topological gap junction                        connectivity can have on the regulation of activity in networks that are                        prone to seizing.For mild perturbation of activity (low noise intensity, blue region), an                        increase in gap junction connectivity can offset the effect of perturbation                        and restore low firing rate, thus suppressing potential seizures. On the                        other hand, for strong perturbation (strong noise intensity, red region), an                        addition of gap junctions is likely to result in seizure escalation.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3105095&req=5

pone-0020572-g007: Schematic presentation of the effect that topological gap junction connectivity can have on the regulation of activity in networks that are prone to seizing.For mild perturbation of activity (low noise intensity, blue region), an increase in gap junction connectivity can offset the effect of perturbation and restore low firing rate, thus suppressing potential seizures. On the other hand, for strong perturbation (strong noise intensity, red region), an addition of gap junctions is likely to result in seizure escalation.

Mentions: A significant body of data from in-vitro experiments and in-vivo measurements suggests that electrical coupling between neurons by means of gap junctions may play important role in information processing [29], [30], but also in the initiation and escalation of epileptic seizures [16]. Computational models suggest that gap junctions could be responsible for the generation of fast oscillations that precede seizures [31]. In physiological preparations, the expression of gap junctions was increased following the experimentally induced model of epilepsy [20]; thus, seizure in itself could be responsible for the increased gap junction content. Thus, while there is a consensus regarding the importance of gap junction communication in epilepsy, the causal link between enhanced gap junction expression and the emergence of seizures is still missing. Our studies suggest a possible new role for neuronal gap junctions that contrast a common view according to which this mode of communication is a pure epileptogenic factor promoting seizure activity. We posit that in experimental models of epileptic seizures, an initial increase in gap junction content between the neurons could represent an adaptive response by which the network tries to reduce the effects of transient aberrant neuronal activity. For relatively weak and transient perturbations of activity, such adaptive response can help to suppress the undesirable hyper-excitation; however, if the perturbation of activity is too strong and/or too persistent, an increase in gap junction content will lead to the escalation of seizure (Figure 7).


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

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

Schematic presentation of the effect that topological gap junction                        connectivity can have on the regulation of activity in networks that are                        prone to seizing.For mild perturbation of activity (low noise intensity, blue region), an                        increase in gap junction connectivity can offset the effect of perturbation                        and restore low firing rate, thus suppressing potential seizures. On the                        other hand, for strong perturbation (strong noise intensity, red region), an                        addition of gap junctions is likely to result in seizure escalation.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020572-g007: Schematic presentation of the effect that topological gap junction connectivity can have on the regulation of activity in networks that are prone to seizing.For mild perturbation of activity (low noise intensity, blue region), an increase in gap junction connectivity can offset the effect of perturbation and restore low firing rate, thus suppressing potential seizures. On the other hand, for strong perturbation (strong noise intensity, red region), an addition of gap junctions is likely to result in seizure escalation.
Mentions: A significant body of data from in-vitro experiments and in-vivo measurements suggests that electrical coupling between neurons by means of gap junctions may play important role in information processing [29], [30], but also in the initiation and escalation of epileptic seizures [16]. Computational models suggest that gap junctions could be responsible for the generation of fast oscillations that precede seizures [31]. In physiological preparations, the expression of gap junctions was increased following the experimentally induced model of epilepsy [20]; thus, seizure in itself could be responsible for the increased gap junction content. Thus, while there is a consensus regarding the importance of gap junction communication in epilepsy, the causal link between enhanced gap junction expression and the emergence of seizures is still missing. Our studies suggest a possible new role for neuronal gap junctions that contrast a common view according to which this mode of communication is a pure epileptogenic factor promoting seizure activity. We posit that in experimental models of epileptic seizures, an initial increase in gap junction content between the neurons could represent an adaptive response by which the network tries to reduce the effects of transient aberrant neuronal activity. For relatively weak and transient perturbations of activity, such adaptive response can help to suppress the undesirable hyper-excitation; however, if the perturbation of activity is too strong and/or too persistent, an increase in gap junction content will lead to the escalation of seizure (Figure 7).

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