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A small molecule activator of Na v 1.1 channels increases fast‐spiking interneuron excitability and GABAergic transmission in vitro and has anti‐convulsive effects in vivo
Author(s) -
Frederiksen Kristen,
Lu Dunguo,
Yang Jinhui,
Jensen Henrik Sindal,
Bastlund Jesper Frank,
Larsen Peter Hjørringgaard,
Liu Henry,
Crestey François,
Dekermendjian Kim,
Badolo Lassina,
Laursen Morten,
Hougaard Charlotte,
Yang Charles,
Svenstrup Niels,
Grunnet Morten
Publication year - 2017
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.13626
Subject(s) - inhibitory postsynaptic potential , gabaergic , neuroscience , interneuron , activator (genetics) , hippocampal formation , neurotransmission , chemistry , gamma aminobutyric acid , in vivo , disinhibition , parvalbumin , excitatory postsynaptic potential , biophysics , biology , receptor , biochemistry , microbiology and biotechnology
Na v 1.1 ( SCN 1A ) channels primarily located in gamma‐aminobutyric acid ( GABA )ergic fast‐spiking interneurons are pivotal for action potential generation and propagation in these neurons. Inappropriate function of fast‐spiking interneurons, leading to disinhibition of pyramidal cells and network desynchronization, correlates with decreased cognitive capability. Further, reduced functionality of Na v 1.1 channels is linked to various diseases in the central nervous system. There is, at present, however no subtype selective pharmacological activators of Na v 1.1 channels available for studying pharmacological modulation of interneuron function. In the current study, we identified a small molecule Na v 1.1 activator, 3‐amino‐5‐(4‐methoxyphenyl)thiophene‐2‐carboxamide, named AA 43279, and provided an in vitro to in vivo characterization of the compound. In HEK ‐293 cells expressing human Na v 1.1 channels, AA 43279 increased the Na v 1.1‐mediated current in a concentration‐dependent manner mainly by impairing the fast inactivation kinetics of the channels. In rat hippocampal brain slices, AA 43279 increased the firing activity of parvalbumin‐expressing, fast‐spiking GABA ergic interneurons and increased the spontaneous inhibitory post‐synaptic currents ( sIPSC s) recorded from pyramidal neurons. When tested in vivo , AA 43279 had anti‐convulsive properties in the maximal electroshock seizure threshold test. AA 43279 was tested for off‐target effects on 72 different proteins, including Na v 1.2, Na v 1.4, Na v 1.5, Na v 1.6 and Na v 1.7 and exhibited reasonable selectivity. Taken together, AA 43279 might constitute a valuable tool compound for revealing biological functions of Na v 1.1 channels.