title: Mis-expression of the BK K(+) channel disrupts suprachiasmatic nucleus circuit rhythmicity and alters clock-controlled behavior.
abstract: In mammals, almost all aspects of circadian rhythmicity are attributed to activity in a discrete neural circuit of the hypothalamus, the suprachiasmatic nucleus (SCN). A 24-h rhythm in spontaneous firing is the fundamental neural intermediary to circadian behavior, but the ionic mechanisms that pattern circuit rhythmicity, and the integrated impact on behavior, are not well studied. Here, we demonstrate that daily modulation of a major component of the nighttime-phased suppressive K(+) current, encoded by the BK Ca(2+)-activated K(+) current channel (K(Ca)1.1 or Kcnma1), is a critical arbiter of circadian rhythmicity in the SCN circuit. Aberrant induction of BK current during the day in transgenic mice using a Per1 promoter (Tg-BK(R207Q)) reduced SCN firing or silenced neurons, decreasing the circadian amplitude of the ensemble circuit rhythm. Changes in cellular and circuit excitability in Tg-BK(R207Q) SCNs were correlated with elongated behavioral active periods and enhanced responses to phase-shifting stimuli. Unexpectedly, despite the severe reduction in circuit amplitude, circadian behavioral amplitudes in Tg-BK(R207Q) mice were relatively normal. These data demonstrate that downregulation of the BK current during the day is essential for the high amplitude neural activity pattern in the SCN that restricts locomotor activity to the appropriate phase and maintains the clock's robustness against perturbation. However, a residually rhythmic subset prevails over the ensemble circuit to drive the fundamental circadian behavioral rhythm.
authors.affiliation: Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
authors.forename: Jenna R
authors.initials: JR
authors.lastname: Montgomery
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Whitt
authors.forename: Breanne N
authors.initials: BN
authors.lastname: Wright
authors.forename: Michael H
authors.initials: MH
authors.lastname: Lai
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Meredith
mesh_terms: D000200:Action Potentials; D019943:Amino Acid Substitution; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D057906:Circadian Clocks; D002940:Circadian Rhythm; D015870:Gene Expression; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D018408:Patch-Clamp Techniques; D013493:Suprachiasmatic Nucleus / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: C465449:Kcnma1 protein, mouse; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits