TOPIC

A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons

Journal

The Journal of Pharmacological and Experimental Therapeutics

Author(s)

Marcelo D. Rosato-Siri, Erika Zambello, Chiara Mutinelli, Nicoletta Garbati, Roberto Benedetti, Laura Aldegheri, Francesca Graziani, Caterina Virginio, Giuseppe Alvaro and Charles H. Large

Year

2015

Kv3.1 and Kv3.2 high voltage-activated potassium channels, which display fast activation and deactivation kinetics, are known to make a crucial contribution to the fast-spiking phenotype of certain neurons. Pharmacological experiments
show that the blockade of native Kv3 currents with low concentrations of etraethylammonium or 4-aminopyridine impairs
the expression of this firing phenotype. In particular, Kv3¬†channels are highly expressed by fast-spiking, arvalbuminpositive¬†interneurons in corticolimbic brain circuits, which modulate¬†the synchronization of cortical circuits and the generation¬†of brain rhythms. Here, we describe a novel small molecule,¬†(5R)-5-ethyl-3-(6-{[4-methyl-3-(methyloxy)phenyl]oxy}-3-pyridinyl)-¬†2,4-imidazolidinedione (AUT1), which modulates Kv3.1 and¬†Kv3.2 channels in human recombinant and rodent native¬†neurons. AUT1 increased whole currents mediated by human¬†Kv3.1b and Kv3.2a channels, with a concomitant leftward shift¬†in the voltage dependence of activation. A less potent effect was¬†observed on hKv3.3 currents. In mouse somatosensory cortex¬†slices in vitro, AUT1 rescued the fast-spiking phenotype of¬†parvalbumin-positive‚Äďfast-spiking interneurons following an¬†impairment of their firing capacity by blocking a proportion of¬†Kv3 channels with a low concentration of tetraethylammonium.¬†Notably, AUT1 had no effect on interneuron firing when applied¬†alone. Together, these data confirm the role played by Kv3¬†channels in the regulation of the firing phenotype of somatosensory
interneurons and suggest that AUT1 and other Kv3 modulators could represent a new and promising therapeutic
approach to the treatment of disorders associated with dysfunction of inhibitory feedback in corticolimbic circuits, such as
schizophrenia.

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