Disease-associated KCNMA1 variants decrease circadian clock robustness in channelopathy mouse models

• Published in: The Journal of general physiology Vol. 155; no. 11; p. 1
• Main Authors: Dinsdale, Ria L, Roache, Cooper E, Meredith, Andrea L
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 06.11.2023
• Subjects: Animal models; Animals; Calcium; Calcium channels (voltage-gated); Cellular physiology; Channel gating; Channelopathies; Channelopathy; Circadian Clocks - genetics; Circadian rhythm; Circadian rhythms; Communication; Disease Models, Animal; Dyskinesia; Humans; Ion Channels in Context; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - genetics; Large-Conductance Calcium-Activated Potassium Channels; Mice; Motor Activity; Pathophysiology; Potassium channels (voltage-gated); Suprachiasmatic nucleus; Systems physiology; Wheel running
• ISSN: 0022-1295; 1540-7748
• DOI: 10.1085/jgp.202313357

KCNMA1 encodes the voltage- and calcium-activated K+ (BK) channel, which regulates suprachiasmatic nucleus (SCN) neuronal firing and circadian behavioral rhythms. Gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity disrupt circadian behavior, but the effect of human disease-associated KCNMA1 channelopathy variants has not been studied on clock function. Here, we assess circadian behavior in two GOF and one LOF mouse lines. Heterozygous Kcnma1N999S/WT and homozygous Kcnma1D434G/D434G mice are validated as GOF models of paroxysmal dyskinesia (PNKD3), but whether circadian rhythm is affected in this hypokinetic locomotor disorder is unknown. Conversely, homozygous LOF Kcnma1H444Q/H444Q mice do not demonstrate PNKD3. We assessed circadian behavior by locomotor wheel running activity. All three mouse models were rhythmic, but Kcnma1N999S/WT and Kcnma1D434G/D434G showed reduced circadian amplitude and decreased wheel activity, corroborating prior studies focused on acute motor coordination. In addition, Kcnma1D434G/D434G mice had a small decrease in period. However, the phase-shifting sensitivity for both GOF mouse lines was abnormal. Both Kcnma1N999S/WT and Kcnma1D434G/D434G mice displayed increased responses to light pulses and took fewer days to re-entrain to a new light:dark cycle. In contrast, the LOF Kcnma1H444Q/H444Q mice showed no difference in any of the circadian parameters tested. The enhanced sensitivity to phase-shifting stimuli in Kcnma1N999S/WT and Kcnma1D434G/D434G mice was similar to other Kcnma1 GOF mice. Together with previous studies, these results suggest that increasing BK channel activity decreases circadian clock robustness, without rhythm ablation.