TY - JOUR
T1 - Impaired action potential initiation in GABAergic interneurons causes hyperexcitable networks in an epileptic mouse model carrying a human Nav1.1 mutation
AU - Hedrich, Ulrike B S
AU - Liautard, Camille
AU - Kirschenbaum, Daniel
AU - Pofahl, Martin
AU - Lavigne, Jennifer
AU - Liu, Yuanyuan
AU - Theiss, Stephan
AU - Slotta, Johannes
AU - Escayg, Andrew
AU - Dihné, Marcel
AU - Beck, Heinz
AU - Mantegazza, Massimo
AU - Lerche, Holger
PY - 2014/11/5
Y1 - 2014/11/5
N2 - 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 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.
AB - 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 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.
KW - Epilepsy
KW - Genetics
KW - Ion channel
KW - Mouse model
KW - Network activity
UR - http://www.scopus.com/inward/record.url?scp=84908537805&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84908537805&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0721-14.2014
DO - 10.1523/JNEUROSCI.0721-14.2014
M3 - Article
C2 - 25378155
AN - SCOPUS:84908537805
VL - 34
SP - 14874
EP - 14889
JO - Journal of Neuroscience
JF - Journal of Neuroscience
SN - 0270-6474
IS - 45
ER -