Format

Send to

Choose Destination
J Neurosci. 2014 Nov 5;34(45):14874-89. doi: 10.1523/JNEUROSCI.0721-14.2014.

Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation.

Author information

1
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany.
2
Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence Ion Channel Science and Therapeutics, CNRS UMR 7275, 06560 Valbonne, France, University of Nice Sophia Antipolis, 06103 Nice, France.
3
Department of Epileptology, University of Bonn Medical Center, 53105 Bonn, Germany, German Center for Neurodegenerative Diseases within the Helmholtz Association, 53175 Bonn, Germany.
4
Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany, RESULT Medical, 40219 Düsseldorf, Germany, and.
5
Department of Human Genetics, Emory University, Atlanta, Georgia 30322.
6
Institute of Molecular and Cellular Pharmacology, Laboratory of Excellence Ion Channel Science and Therapeutics, CNRS UMR 7275, 06560 Valbonne, France, University of Nice Sophia Antipolis, 06103 Nice, France, holger.lerche@uni-tuebingen.de mantegazza@ipmc.cnrs.fr.
7
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany, holger.lerche@uni-tuebingen.de mantegazza@ipmc.cnrs.fr.

Abstract

Mutations in SCN1A and other ion channel genes can cause different epileptic phenotypes, but the precise mechanisms underlying the development of hyperexcitable networks are largely unknown. Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans. We found a ubiquitous hypoexcitability of interneurons in thalamus, cortex, and hippocampus, without detectable changes in excitatory neurons. Interestingly, somatic Na(+) channels in interneurons and persistent Na(+) currents were not significantly changed. Instead, the key mechanism of interneuron dysfunction was a deficit of action potential initiation at the axon initial segment that was identified by analyzing action potential firing. This deficit increased with the duration of firing periods, suggesting that increased slow inactivation, as recorded for recombinant mutated channels, could play an important role. The deficit in interneuron firing caused reduced action potential-driven inhibition of excitatory neurons as revealed by less frequent spontaneous but not miniature IPSCs. Multiple approaches indicated increased spontaneous thalamocortical and hippocampal network activity in mutant mice, as follows: (1) more synchronous and higher-frequency firing was recorded in primary neuronal cultures plated on multielectrode arrays; (2) thalamocortical slices examined by field potential recordings revealed spontaneous activities and pathological high-frequency oscillations; and (3) multineuron Ca(2+) imaging in hippocampal slices showed increased spontaneous neuronal activity. Thus, an interneuron-specific generalized defect in action potential initiation causes multisystem disinhibition and network hyperexcitability, which can well explain the occurrence of seizures in the studied mouse model and in patients carrying this mutation.

KEYWORDS:

epilepsy; genetics; ion channel; mouse model; network activity

PMID:
25378155
PMCID:
PMC4220023
DOI:
10.1523/JNEUROSCI.0721-14.2014
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center