Increased Neuronal Firing in Computer Simulations of Sodium Channel Mutations That Cause Generalized Epilepsy With Febrile Seizures Plus

Spampanato, Jay; Aradi, Ildikó; Soltész, Iván; Goldin, Alan L.

doi:10.1152/jn.00982.2003

Cited by 65 publications

(53 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…To determine the physiological effects of the changes in sodium channel kinetics caused by the D1866Y mutation, Hodgkin-Huxley-type conductance-based models of spiking neurons were constructed using the NEURON simulation software (Hines and Carnevale, 1997). Single-compartment models of neuronal soma were constructed, and sodium and delayed rectifier potassium channels were included as described previously (Spampanato et al, 2004).…”

Section: Methodsmentioning

confidence: 99%

“…The models included wild-type Na v 1.1 or D1866Y mutant channels with kinetics and voltage dependencies characterized in this study and delayed rectifier K ϩ channels with kinetics similar to those used previously (Spampanato et al, 2004). In all cases, the modeled sodium channel kinetics represent those that were determined during coexpression of the ␤1 subunit.…”

Section: Methodsmentioning

confidence: 99%

“…Second, the ␤1 subunit has a clear and easily quantifiable effect on the properties of ␣ subunit sodium channels in oocytes, so that we could reliably determine whether the ␣ subunit mutation altered modulation by ␤1. Third, the data could be directly compared with our previous results for three other GEFSϩ mutations with respect to both the effects on sodium channel properties and the predicted effects on neuronal firing using a computational model (Spampanato et al, 2001(Spampanato et al, , 2003(Spampanato et al, , 2004. It is important to note that although the oocyte expression system provides a powerful means to determine biophysical differences between mutant and wild-type channels, there have been functional differences as well as similarities between observations in oocytes and in mammalian-transfected cells for some mutants (Spampanato et al, 2001(Spampanato et al, , 2003Lossin et al, 2002).…”

Section: The D1866y Mutation Does Not Alter the Voltage Dependence Ofmentioning

confidence: 99%

“…Computational analysis of three GEFSϩ mutations has previously shown that each mutation had a different effect on the threshold for firing a single action potential, but all the mutations increased the propensity of the model neuron to fire multiple action potentials (Spampanato et al, 2004). When analyzed in a similar manner, the D1866Y mutation did not have any effect on the threshold for firing a single action potential (70 pA for both mutant and wild-type channels), nor did it increase the propen- sity of the model neuron to fire multiple action potentials (data not shown).…”

Section: The D1866y Mutant Channels Produce a Hyperexcitable Model Nementioning

confidence: 99%

See 3 more Smart Citations

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

Spampanato¹,

Kearney²,

Haan³

et al. 2004

J. Neurosci.

150

142

View full text Add to dashboard Cite

A mutation in the sodium channel SCN1A was identified in a small Italian family with dominantly inherited generalized epilepsy with febrile seizures plus (GEFSϩ). The mutation, D1866Y, alters an evolutionarily conserved aspartate residue in the C-terminal cytoplasmic domain of the sodium channel ␣ subunit. The mutation decreased modulation of the ␣ subunit by ␤1, which normally causes a negative shift in the voltage dependence of inactivation in oocytes. There was less of a shift with the mutant channel, resulting in a 10 mV difference between the wild-type and mutant channels in the presence of ␤1. This shift increased the magnitude of the window current, which resulted in more persistent current during a voltage ramp. Computational analysis suggests that neurons expressing the mutant channels will fire an action potential with a shorter onset delay in response to a threshold current injection, and that they will fire multiple action potentials with a shorter interspike interval at a higher input stimulus. These results suggest a causal relationship between a positive shift in the voltage dependence of sodium channel inactivation and spontaneous seizure activity. Direct interaction between the cytoplasmic C-terminal domain of the wild-type ␣ subunit with the ␤1 or ␤3 subunit was first demonstrated by yeast two-hybrid analysis. The SCN1A peptide K1846-R1886 is sufficient for ␤ subunit interaction. Coimmunoprecipitation from transfected mammalian cells confirmed the interaction between the C-terminal domains of the ␣ and ␤1 subunits. The D1866Y mutation weakens this interaction, demonstrating a novel molecular mechanism leading to seizure susceptibility.

show abstract

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: The D1866y Mutation Does Not Alter the Voltage Dependence Ofmentioning

confidence: 99%

Section: The D1866y Mutant Channels Produce a Hyperexcitable Model Nementioning

confidence: 99%

See 2 more Smart Citations

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

Spampanato¹,

Kearney²,

Haan³

et al. 2004

J. Neurosci.

150

142

View full text Add to dashboard Cite

show abstract

“…41 Computer simulations, however, suggest that the changes can explain increased neuronal firing. 42 Two other severe syndromes of early life are associated with mutations in SCN1A. Severe myoclonic epilepsy of infancy (SMEI) manifests many seizure types often evolving into a malignant syndrome.…”

Section: Voltage-gated Sodium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

View full text Add to dashboard Cite

Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

show abstract

Thrombin facilitates seizures through activation of persistent sodium current

Isaeva¹,

Hernan²,

Isaev³

et al. 2012

Annals of Neurology

View full text Add to dashboard Cite

Objective An epileptic seizure is frequently the presenting sign of intracerebral hemorrhage (ICH) caused by stroke, head trauma, hypertension and a wide spectrum of disorders. However the cellular mechanisms responsible for occurrence of seizures during ICH have not been established. During intracerebral bleeding, blood constituents enter the neuronal tissue and produce both an acute and delayed effect on brain functioning. Among the blood components only thrombin has been shown to evoke seizures immediately after entering brain tissue. In the present study we tested the hypothesis that thrombin increase neuronal excitability in the immature brain through alteration of voltage-gated sodium channels. Methods The thrombin effect on neuronal excitability and voltage-gated sodium channels was assessed using extracellular and intracellular recording techniques in the hippocampal slice preparation of immature rats. Results We show that thrombin increased neuronal excitability in the immature hippocampus in an NMDA-independent manner. Application of thrombin did not alter transient voltage-gated sodium channels and action potential threshold. However thrombin significantly depolarized the membrane potential and produced a hyperpolarizing shift of TTX sensitive persistent voltage-gated sodium channel activation. This effect of thrombin was attenuated by application of protease-activated receptor-1 and protein kinase C antagonists. Interpretation Our data indicates that thrombin amplifies the persistent voltage-gated sodium current affecting resting membrane potential and seizure threshold at the network level. Our results provide a novel explanation as to how ICH in newborns results in seizures, which may provide avenues for therapeutic intervention in the prevention of post-ICH seizures.

show abstract

Increased Neuronal Firing in Computer Simulations of Sodium Channel Mutations That Cause Generalized Epilepsy With Febrile Seizures Plus

Cited by 65 publications

References 50 publications

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

A Novel Epilepsy Mutation in the Sodium ChannelSCN1AIdentifies a Cytoplasmic Domain for β Subunit Interaction

Molecular Targets for Antiepileptic Drug Development

Thrombin facilitates seizures through activation of persistent sodium current

Contact Info

Product

Resources

About