Kv12-Encoded K ⁺ Channels Drive the Day-Night Switch in the Repetitive Firing Rates of SCN Neurons

Feb 13, 2023bioRxiv : the preprint server for biology

Kv12 Potassium Channels Control Daily Changes in the Firing Rates of Brain Clock Neurons

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Abstract

Mean nighttime repetitive firing rates in SCN neurons from mice with disruptions in the Kv12.1 or Kv12.2 genes were higher than in wild type neurons.

Disruptions in Kv12.1 or Kv12.2 resulted in an elimination of the typical day-night difference in repetitive firing rates of SCN neurons.
Mean daytime firing rates were similar across Kv12.1, Kv12.2, and wild type SCN neurons.
Kv12-encoded currents were found to have higher densities at night compared to daytime in wild type SCN neurons.
Blocking Kv12-encoded currents increased nighttime repetitive firing rates but had no effect during the day.
Locomotor activity remained rhythmic in mice with Kv12 disruptions, indicating that other mechanisms may maintain circadian rhythms.

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Considerable evidence suggests that day-night rhythms in the functional expression of subthreshold potassium (K) channels regulate daily oscillations in the rates of spontaneous action potential firing of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals. The Kconductance(s) driving these daily rhythms in repetitive firing rates, however, have not been identified. To test the hypothesis that subthreshold Kv12.1/Kv12.2-encoded Kchannels play a role, we obtained current-clamp recordings from SCN neurons in slices prepared from adult mice harboring targeted disruptions in the(Kv12.1) or(Kv12.2) locus. We found that mean nighttime repetitive firing rates were higher in Kv12.1and Kv12.2, than in wild type (WT), SCN neurons. In marked contrast, mean daytime repetitive firing rates were similar in Kv12.1, Kv12.2and WT SCN neurons, and the day-night difference in mean repetitive firing rates, a hallmark feature of WT SCN neurons, was eliminated in Kv12.1and Kv12.2SCN neurons. Similar results were obtained withshRNA-mediated acute knockdown of Kv12.1 or Kv12.2 in adult SCN neurons. Voltage-clamp experiments revealed that Kv12-encoded current densities in WT SCN neurons are higher at night than during the day. In addition, pharmacological block of Kv12-encoded currents increased the mean repetitive firing rate of nighttime, but not daytime, in WT SCN neurons. Dynamic clamp-mediated subtraction of modeled Kv12-encoded currents also selectively increased the mean repetitive firing rates of nighttime WT SCN neurons. Despite the elimination of nighttime decrease in the mean repetitive firing rates of SCN neurons, however, locomotor (wheel-running) activity remained rhythmic in Kv12.1, Kv12.2, Kv12.1-targeted shRNA-expressing, and Kv12.2-targeted shRNA-expressing animals. + + + -/--/--/--/--/--/--/--/--/--/-Kcnh8Kcnh3in vivo

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Kv12-Encoded K ⁺ Channels Drive the Day-Night Switch in the Repetitive Firing Rates of SCN Neurons

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