A small molecule activator of Nav1.1 channels increases fast-spiking interneuron excitability and GABAergic transmission in vitro and has anti-convulsive effects in vivo

著者: Kristen Frederiksen, Lu Dunguo, Jinhui Yang, Henrik Sindal Jensen, Jesper Frank Bastlund, Peter Hjørringgaard Larsen, Liu Henry, Kim Dekermendjian, Lassina Badolo, Morten Laursen, Charlotte Hougaard, Charles Yang, Niels Svenstrup, Morten Grunnet

NaV1.1 (SCN1A) 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 NaV1.1 channels is linked to various diseases in the central nervous system. There is, at present, however no subtype selective pharmacological activators of NaV1.1 channels available for studying pharmacological modulation of interneuron function. In the current study we identified a small molecule NaV1.1 activator, 3-Amino-5-(4-methoxyphenyl)thiophene-2-carboxamide, named AA43279, and provided an in vitro to in vivo characterization of the compound. In HEK-293 cells expressing human NaV1.1 channels, AA43279 increased the NaV1.1-mediated current in a concentration-dependent manner mainly by impairing the fast inactivation kinetics of the channels. In rat hippocampal brain slices, AA43279 increased the firing activity of parvalbumin-expressing, fast-spiking GABAergic interneurons and increased the spontaneous inhibitory post-synaptic currents (sIPSCs) recorded from pyramidal neurons. When tested in vivo, AA43279 had anti-convulsive properties in the maximal electroshock seizure threshold test. AA43279 was tested for off-target effects on 72 different proteins, including NaV1.2, NaV1.4, NaV1.5, NaV1.6 and NaV1.7, and exhibited reasonable selectivity. Taken together, AA43279 might constitute a valuable tool compound for revealing biological functions of NaV1.1 channels.