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

Na_V1.1 (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 Na_V1.1 channels is linked to various diseases in the central nervous system. There is, at present, however no subtype selective pharmacological activators of Na_V1.1 channels available for studying pharmacological modulation of interneuron function. In the current study we identified a small molecule Na_V1.1 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 Na_V1.1 channels, AA43279 increased the Na_V1.1-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 Na_V1.2, Na_V1.4, Na_V1.5, Na_V1.6 and Na_V1.7, and exhibited reasonable selectivity. Taken together, AA43279 might constitute a valuable tool compound for revealing biological functions of Na_V1.1 channels.