Enhanced in vitro CA1 network activity in a sodium channel β1(C121W) subunit model of genetic epilepsy.

Abstract

OBJECTIVE:

A NaV β1(C121W) mouse model of human genetic epilepsy has enhanced neuronal excitability and temperature sensitivity attributed to a decreased threshold for action potential firing in the axon initial segment. To investigate the network consequences of this neuronal dysfunction and to establish a genetic disease state model we developed an in vitro assay to investigate CA1 network properties and antiepileptic drug sensitivity.

METHODS:

CA1 network oscillations were induced by tetanic stimulation and average number of spikes, interspike interval (ISI), duration, and latency were measured in slices from control and NaV β1(C121W) heterozygous mice in the presence and absence of retigabine or carbamazepine. Retigabine was also tested in a thermogenic seizure model.

RESULTS:

Oscillations were reliably induced by tetanic stimulation and were maintained after severing connections between CA3 and CA1, suggesting a local recurrent circuit. Blocking α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), γ-aminobutyric acid receptor A (GABAA ), Ih , and T-type Ca(2+) channels/receptors reduced the number of spikes. Slices from NaV β1(C121W) heterozygous mice displayed several hallmarks of increased network excitability including increases in duration of the oscillation, the number and frequency of spikes and a decrease in their onset latency. The effect of genotype on network excitability was temperature sensitive, as it was seen only at elevated temperatures. Carbamazepine and retigabine were more effective in reducing network excitability in slices from NaV β1(C121W) heterozygous mice. Retigabine appeared to be more effective in suppressing time to thermogenic seizures in NaV β1(C121W) heterozygous mice compared to wild-type (WT) controls.

SIGNIFICANCE:

Hippocampal networks of the NaV β1(C121W) heterozygous mouse model of genetic epilepsy show enhanced excitability consistent with earlier single neuron studies bridging important scales of brain complexity relevant to seizure genesis. Altered pharmacosensitivity further suggests that genetic epilepsy models may be useful in the development of novel antiepileptic drugs that target disease state pathology. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

• Authors: Robert J Hatch, Christopher A Reid, Steven Petrou
• Journal: Epilepsia (Epilepsia) Vol. 55 Issue 4 Pg. 601-8 (Apr 2014) ISSN: 1528-1167 [Electronic] United States
• PMID: 24605816 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

Chemical References

• Anticonvulsants
• Carbamates
• Phenylenediamines
• Scn1b protein, mouse
• Voltage-Gated Sodium Channel beta-1 Subunit
• ezogabine
• Carbamazepine

Topics

• Action Potentials (drug effects, physiology)
• Animals
• Anticonvulsants (pharmacology, therapeutic use)
• CA1 Region, Hippocampal (drug effects, pathology)
• Carbamates (pharmacology, therapeutic use)
• Carbamazepine (pharmacology, therapeutic use)
• Disease Models, Animal
• Epilepsy (drug therapy, genetics, physiopathology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Nerve Net (drug effects, pathology)
• Organ Culture Techniques
• Phenylenediamines (pharmacology, therapeutic use)
• Up-Regulation (genetics)
• Voltage-Gated Sodium Channel beta-1 Subunit (biosynthesis, genetics)