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dc.contributor.authorDinsdale, Ria L.
dc.contributor.authorRoache, Cooper E.
dc.contributor.authorMeredith, Andrea L.
dc.descriptionPoster presented at SGP, September 7-11, 2022en_US
dc.description.abstractKCNMA1 encodes the large conductance calcium- and voltage-activated potassium (BK) channel which regulates suprachiasmatic nucleus neural excitability and circadian behavioural rhythms. Some gain-of-function (GOF) mutations disrupt circadian behaviour and clock function, evidenced by an increase in behavioural active period and amplified response to phase-shifting stimuli, with no detectable effect on motor coordination. The KCNMA1-N999S channelopathy patient variant, has been characterized as GOF, and heterozygous mice harbouring BKN999S (KCNMA1N999S/WT) are a validated model of paroxysmal dyskinesia. Whether KCNMA1N999S/WT mice have a disruption of circadian behaviour due to the GOF nature of the mutation has not been tested. Circadian behaviour in wild-type (WT) and KCNMA1N999S/WT littermates was measured by wheel running activity in constant darkness, assessing circadian period (τ) and the circadian amplitude of activity rhythms, as measured by the amplitude of a χ² periodogram and the relative power of the circadian component from the Fourier transform (FFT rPSD). We predict that if the circadian rhythm is disrupted, there would be a reduction in χ² amplitude and FFT rPSD, with a change in τ. Instead, KCNMA1N999S/WT mice display a reduction in χ² amplitude (-17 %) and FFT rPSD (-35 %), but without a τ difference compared to WT. The number of wheel rotations during the active phase decreased in KCNMA1N999S/WT mice (14667 ± 1432, N=14) compared to WT (25094 ± 1848, N=12; P=0.0002, Welch’s t test), suggesting KCNMA1N999S/WT mice have reduced locomotor function. However, when exposed to a phase-shifting zeitgeber, there is a 42-minute greater response to a pulse of light at CT16. KCNMA1N999S/WT mice also re-entrain to a phase-advance of the light:dark cycle (+6L) in 2.5 fewer days than WT. Thus, although no overt difference in circadian rhythm was identified, diminished clock function was detected as an enhanced sensitivity to phase-shifting stimuli, comparable to other GOF models.en_US
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.subject.meshCircadian Rhythmen_US
dc.titleEvaluation of circadian behaviour in the KCNMA1-N999S channelopathy mouse modelen_US

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