Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Na(V)1.1 mutation
| Autor: | Holger Lerche, Martin Pofahl, Stephan Theiss, Camille Liautard, Yuanyuan Liu, Johannes Slotta, Ulrike B. S. Hedrich, Andrew Escayg, Jennifer Lavigne, Heinz Beck, Massimo Mantegazza, Marcel Dihné, Daniel Kirschenbaum |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
metabolism [GABAergic Neurons]
Hippocampus Action Potentials Hippocampal formation metabolism [Axons] physiopathology [Brain] Epilepsy Mice physiopathology [Nerve Net] Premovement neuronal activity metabolism [Calcium] GABAergic Neurons SCN1A protein human Cells Cultured physiology [GABAergic Neurons] metabolism [Interneurons] metabolism [Nerve Net] Action potential initiation General Neuroscience metabolism [NAV1.1 Voltage-Gated Sodium Channel] Brain Articles medicine.anatomical_structure Excitatory postsynaptic potential cytology [Nerve Net] metabolism [Epilepsy] Interneuron genetics [Epilepsy] physiology [Interneurons] genetics [NAV1.1 Voltage-Gated Sodium Channel] Biology physiopathology [Epilepsy] Interneurons medicine Animals Humans ddc:610 physiology [Axons] cytology [Brain] medicine.disease Axon initial segment Axons Mice Inbred C57BL NAV1.1 Voltage-Gated Sodium Channel nervous system Inhibitory Postsynaptic Potentials metabolism [Brain] Mutation Calcium Nerve Net Neuroscience |
| Zdroj: | The journal of neuroscience 34(45), 14874-14889 (2014). doi:10.1523/JNEUROSCI.0721-14.2014 |
| DOI: | 10.1523/JNEUROSCI.0721-14.2014 |
| Popis: | Mutations inSCN1Aand 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 anSCN1Amouse 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 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. |
| Databáze: | OpenAIRE |
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