title: A Novel Modulator of Kv3 Potassium Channels Regulates the Firing of Parvalbumin-Positive Cortical Interneurons.
abstract: 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 tetraethylammonium or 4-aminopyridine impairs the expression of this firing phenotype. In particular, Kv3 channels are highly expressed by fast-spiking, parvalbumin-positive 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-fast-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.
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.).
authors.forename: Marcelo D
authors.initials: MD
authors.lastname: Rosato-Siri
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.).
authors.forename: Erika
authors.initials: E
authors.lastname: Zambello
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.).
authors.forename: Chiara
authors.initials: C
authors.lastname: Mutinelli
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.).
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Garbati
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.).
authors.forename: Roberto
authors.initials: R
authors.lastname: Benedetti
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.).
authors.forename: Laura
authors.initials: L
authors.lastname: Aldegheri
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.).
authors.forename: Francesca
authors.initials: F
authors.lastname: Graziani
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.).
authors.forename: Caterina
authors.initials: C
authors.lastname: Virginio
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.).
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Alvaro
authors.affiliation: Autifony s.r.l., Verona, Italy (M.D.R.-S., G.A.); Aptuit s.r.l., Verona, Italy (E.Z., C.M., N.G., R.B., L.A., C.V.); Medicines Research Centre, GlaxoSmithKline S.p.A., Verona, Italy (F.G.); and Autifony Therapeutics Limited, Imperial College Incubator, London, United Kingdom (C.H.L.) charles.large@autifony.com.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Large
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D006801:Humans; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010320:Parvalbumins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D051670:Shaw Potassium Channels / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D013003:Somatosensory Cortex / Q000187:drug effects / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology
chemical_list: D010320:Parvalbumins; D011994:Recombinant Proteins; D051670:Shaw Potassium Channels; D054852:Small Molecule Libraries; D019789:Tetraethylammonium