期刊
JOURNAL OF NEUROSCIENCE
卷 34, 期 45, 页码 14874-14889出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0721-14.2014
关键词
epilepsy; genetics; ion channel; mouse model; network activity
资金
- Deutsche Forschungsgemeinschaft [Le1030/10-1/2, SFB 1089]
- Bundesministerium fur Bildung und Forschung (National Genome Research Network/Epilepsy and Migraine integrated network Grants) [01GS08123, 01GS08122]
- EuroTransBio/ESSENCE [FKZ0315641A]
- European Commission (Grant EPICURE) [LSHM-CT-2006-037315]
- Laboratory of Excellence Ion Channel Science and Therapeutics
- Fondation Recherche Medicale
- National Institute of Neurological Disorders
- Stroke of the National Institutes of Health [R01-NS072221]
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 Na(V)1.1-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 Ca2+ 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.
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