Efficacy loss of the anticonvulsant carbamazepine in mice lacking sodium channel beta subunits via paradoxical effects on persistent sodium currents.

Neuronal excitability is critically determined by the properties of voltage-gated Na(+) currents. Fast transient Na(+) currents (I(NaT)) mediate the fast upstroke of action potentials, whereas low-voltage-activated persistent Na(+) currents (I(NaP)) contribute to subthreshold excitation. Na(+) channels are composed of a pore-forming alpha subunit and beta subunits, which modify the biophysical properties of alpha subunits. We have examined the idea that the presence of beta subunits also modifies the pharmacological properties of the Na(+) channel complex using mice lacking either the beta(1) (Scn1b) or beta(2) (Scn2b) subunit. Classical effects of the anticonvulsant carbamazepine (CBZ), such as the use-dependent reduction of I(NaT) and effects on I(NaT) voltage dependence of inactivation, were unaltered in mice lacking beta subunits. Surprisingly, CBZ induced a small but significant shift of the voltage dependence of activation of I(NaT) and I(NaP) to more hyperpolarized potentials. This novel CBZ effect on I(NaP) was strongly enhanced in Scn1b null mice, leading to a pronounced increase of I(NaP) within the subthreshold potential range, in particular at low CBZ concentrations of 10-30 microm. A combination of current-clamp and computational modeling studies revealed that this effect causes a complete loss of CBZ efficacy in reducing repetitive firing. Thus, beta subunits modify not only the biophysical but also the pharmacological properties of Na(+) channels, in particular with respect to I(NaP). Consequently, altered expression of beta subunits in other neurological disorders may cause altered neuronal sensitivity to drugs targeting Na(+) channels.

From brain to earth and climate systems: small-world interaction networks or not?

We consider recent reports on small-world topologies of interaction networks derived from the dynamics of spatially extended systems that are investigated in diverse scientific fields such as neurosciences, geophysics, or meteorology. With numerical simulations that mimic typical experimental situations, we have identified an important constraint when characterizing such networks: indications of a small-world topology can be expected solely due to the spatial sampling of the system along with the commonly used time series analysis based approaches to network characterization.

Evolving functional network properties and synchronizability during human epileptic seizures.

We assess electrical brain dynamics before, during, and after 100 human epileptic seizures with different anatomical onset locations by statistical and spectral properties of functionally defined networks. We observe a concave-like temporal evolution of characteristic path length and cluster coefficient indicative of a movement from a more random toward a more regular and then back toward a more random functional topology. Surprisingly, synchronizability was significantly decreased during the seizure state but increased already prior to seizure end. Our findings underline the high relevance of studying complex systems from the viewpoint of complex networks, which may help to gain deeper insights into the complicated dynamics underlying epileptic seizures.

State dependent properties of epileptic brain networks: comparative graph-theoretical analyses of simultaneously recorded EEG and MEG.

OBJECTIVE: To investigate whether functional brain networks of epilepsy patients treated with antiepileptic medication differ from networks of healthy controls even during the seizure-free interval. METHODS: We applied different rules to construct binary and weighted networks from EEG and MEG data recorded under a resting-state eyes-open and eyes-closed condition from 21 epilepsy patients and 23 healthy controls. The average shortest path length and the clustering coefficient served as global statistical network characteristics. RESULTS: Independent on the behavioral condition, epileptic brains exhibited a more regular functional network structure. Similarly, the eyes-closed condition was characterized by a more regular functional network structure in both groups. The amount of network reorganization due to behavioral state changes was similar in both groups. Consistent findings could be achieved for networks derived from EEG but hardly from MEG recordings, and network construction rules had a rather strong impact on our findings. CONCLUSIONS: Despite the locality of the investigated processes epileptic brain networks differ in their global characteristics from non-epileptic brain networks. Further methodological developments are necessary to improve the characterization of disturbed and normal functional networks. SIGNIFICANCE: An increased regularity and a diminished modulation capability appear characteristic of epileptic brain networks.

Axon initial segment dysfunction in a mouse model of genetic epilepsy with febrile seizures plus.

Febrile seizures are a common childhood seizure disorder and a defining feature of genetic epilepsy with febrile seizures plus (GEFS+), a syndrome frequently associated with Na+ channel mutations. Here, we describe the creation of a knockin mouse heterozygous for the C121W mutation of the beta1 Na+ channel accessory subunit seen in patients with GEFS+. Heterozygous mice with increased core temperature displayed behavioral arrest and were more susceptible to thermal challenge than wild-type mice. Wild-type beta1 was most concentrated in the membrane of axon initial segments (AIS) of pyramidal neurons, while the beta1(C121W) mutant subunit was excluded from AIS membranes. In addition, AIS function, an indicator of neuronal excitability, was substantially enhanced in hippocampal pyramidal neurons of the heterozygous mouse specifically at higher temperatures. Computational modeling predicted that this enhanced excitability was caused by hyperpolarized voltage activation of AIS Na+ channels. This heat-sensitive increased neuronal excitability presumably contributed to the heightened thermal seizure susceptibility and epileptiform discharges seen in patients and mice with beta1(C121W) subunits. We therefore conclude that Na+ channel beta1 subunits modulate AIS excitability and that epilepsy can arise if this modulation is impaired.

Synchronization phenomena in human epileptic brain networks.

Epilepsy is a malfunction of the brain that affects over 50 million people worldwide. Epileptic seizures are usually characterized by an abnormal synchronized firing of neurons involved in the epileptic process. In human epilepsy the exact mechanisms underlying seizure generation are still uncertain as are mechanisms underlying seizure spreading and termination. There is now growing evidence that an improved understanding of the epileptic process can be achieved through the analysis of properties of epileptic brain networks and through the analysis of interactions in such networks. In this overview, we summarize recent methodological developments to assess synchronization phenomena in human epileptic brain networks and present findings obtained from analyses of brain electromagnetic signals recorded in epilepsy patients.

Role of axonal NaV1.6 sodium channels in action potential initiation of CA1 pyramidal neurons.

In many neuron types, the axon initial segment (AIS) has the lowest threshold for action potential generation. Its active properties are determined by the targeted expression of specific voltage-gated channel subunits. We show that the Na+ channel NaV1.6 displays a striking aggregation at the AIS of cortical neurons. To assess the functional role of this subunit, we used Scn8amed mice that are deficient for NaV1.6 subunits but still display prominent Na+ channel aggregation at the AIS. In CA1 pyramidal cells from Scn8amed mice, we found a depolarizing shift in the voltage dependence of activation of the transient Na+ current (INaT), indicating that NaV1.6 subunits activate at more negative voltages than other NaV subunits. Additionally, persistent and resurgent Na+ currents were significantly reduced. Current-clamp recordings revealed a significant elevation of spike threshold in Scn8amed mice as well as a shortening of the estimated delay between spike initiation at the AIS and its arrival at the soma. In combination with simulations using a realistic computer model of a CA1 pyramidal cell, our results imply that a hyperpolarized voltage dependence of activation of AIS NaV1.6 channels is important both in determining spike threshold and localizing spike initiation to the AIS. In addition to altered spike initiation, Scn8amed mice also showed a strongly reduced spike gain as expected with combined changes in persistent and resurgent currents and spike threshold. These results suggest that NaV1.6 subunits at the AIS contribute significantly to its role as spike trigger zone and shape repetitive discharge properties of CA1 neurons.