Abstract
Due to their fast kinetic properties, Kv3.1 voltage gated potassium channels are important in setting and controlling firing frequency in neurons and pivotal in generating high frequency firing of interneurons. Pharmacological activation of Kv3.1 channels may possess therapeutic potential for treatment of epilepsy, hearing disorders, schizophrenia and cognitive impairments.Here we thoroughly investigate the selectivity and positive modulation of the two small molecules, EX15 and RE01, on Kv3 channels. Selectivity studies, conducted in Xenopus laevis oocytes confirmed a positive modulatory effect of the two compounds on Kv3.1 and to a minor extent on Kv3.2 channels. RE01 had no effect on the Kv3.3 and Kv3.4 channels, whereas EX15 had an inhibitory impact on the Kv3.4 mediated current.Voltage-clamp experiments in monoclonal hKv3.1b/HEK293 cells (34 °C) revealed that the two compounds indeed induced larger currents and faster activation kinetics. They also decrease the speed of deactivation and shifted the voltage dependence of activation, to a more negative activation threshold. Application of action potential clamping and repetitive stimulation protocols of hKv3.1b expressing HEK293 cells revealed that EX15 and RE01 significantly increased peak amplitude, half width and decay time of Kv3.1 mediated currents, even during high-frequency action potential clamping (250 Hz).In rat hippocampal slices, EX15 and RE01 increased neuronal excitability in fast-spiking interneurons in dentate gyrus. Action potential frequency was prominently increased at minor depolarizing steps, whereas more marginal effects of EX15 and RE01 were observed after stronger depolarizations.In conclusion, our results suggest that EX15 and RE01 positive modulation of Kv3.1 and Kv3.2 currents facilitate increased firing frequency in fast-spiking GABAergic interneurons.
Highlights
GABAergic interneurons are central in shaping communication and controlling excitability within the central nervous system
Knowing that example 15 (EX15) and RE01 were able to modulate the fast kinetics of Kv3.1 channels, we evaluated the potential of the two compounds to modulate Kv3.1b channel currents during high frequency action potential firing as seen in fast-spiking GABAergic interneurons
As our experiments revealed that EX15 and RE01 increased the deactivation time constants of Kv3.1b channels, it can be speculated that high frequency firing combined with relatively depolarized potentials just prior to the action potential may produce an accumulation of Kv3.1 channels in the open state following compound application
Summary
GABAergic interneurons are central in shaping communication and controlling excitability within the central nervous system. High frequency firing of GABAergic interneurons requires that both the action potentials and the afterhyperpolarizations to be short. Due to their fast activating properties, potassium channels of the Kv3 family are believed to be important in setting and controlling firing frequency in fast spiking neurons (Espinosa et al, 2008; Lenz et al, 1994; Lien and Jonas, 2003; Porcello et al, 2002; Rosato-Siri et al, 2015).
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