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. (20th July 2017)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: European journal of neuroscience. Volume 46:Number 3(2017)
• Page Start: 1887
• Page End: 1896
• Publication Date: 2017-07-20
• Subjects: activators -- interneurons -- maximal electroshock seizures threshold -- SCNA1 -- slice electrophysiology; Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.13626
• Languages: English
• ISSNs: 0953-816X

Abstract

Abstract: Nav 1.1 ( 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 Nav 1.1 channels is linked to various diseases in the central nervous system. There is, at present, however no subtype selective pharmacological activators of Nav 1.1 channels available for studying pharmacological modulation of interneuron function. In the current study, we identified a small molecule Nav 1.1 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 Nav 1.1 channels, AA43279 increased the Nav 1.1‐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 Nav 1.2, Nav 1.4, Nav 1.5, Nav 1.6 and Nav 1.7 and exhibited reasonable selectivity. Taken together, AA43279 might constitute a valuable tool compound for revealing biological functions of Nav 1.1 channels. Abstract : We have identified a small molecule activator of Nav1.1 channels, AA43279. In hippocampal brain slices, AA43279 augments action potential firing from fast‐spiking interneurons and increases the frequency of spontaneous inhibitory post‐synaptic currents recorded in pyramidal neurons. We propose that activators of Nav1.1 channels may restore synaptic transmission under conditions where normal fast‐spiking interneuron function is impaired.