KCNQ3 is the principal target of retigabine in CA1 and subicular excitatory neurons.

Abstract

Retigabine is a first-in-class potassium channel opener approved for patients with epilepsy. Unfortunately, several side effects have limited its use in clinical practice, overshadowing its beneficial effects. Multiple studies have shown that retigabine acts by enhancing the activity of members of the voltage-gated KCNQ (Kv7) potassium channel family, particularly the neuronal KCNQ channels KCNQ2-KCNQ5. However, it is currently unknown whether retigabine's action in neurons is mediated by all KCNQ neuronal channels or by only a subset. This knowledge is necessary to elucidate retigabine's mechanism of action in the central nervous system and its adverse effects and to design more effective and selective retigabine analogs. In this study, we show that the action of retigabine in excitatory neurons strongly depends on the presence of KCNQ3 channels. Deletion of Kcnq3 severely limited the ability of retigabine to reduce neuronal excitability in mouse CA1 and subiculum excitatory neurons. In addition, we report that in the absence of KCNQ3 channels, retigabine can enhance CA1 pyramidal neuron activity, leading to a greater number of action potentials and reduced spike frequency adaptation; this finding further supports a key role of KCNQ3 channels in mediating the action of retigabine. Our work provides new insight into the action of retigabine in forebrain neurons, clarifying retigabine's action in the nervous system.NEW & NOTEWORTHY Retigabine has risen to prominence as a first-in-class potassium channel opener approved by the Food and Drug Administration, with potential for treating multiple neurological disorders. Here, we demonstrate that KCNQ3 channels are the primary target of retigabine in excitatory neurons, as deleting these channels greatly diminishes the effect of retigabine in pyramidal neurons. Our data provide the first indication that retigabine controls neuronal firing properties primarily through KCNQ3 channels.