title: Sustaining sleep spindles through enhanced SK2-channel activity consolidates sleep and elevates arousal threshold.
abstract: Sleep spindles are synchronized 11-15 Hz electroencephalographic (EEG) oscillations predominant during nonrapid-eye-movement sleep (NREMS). Rhythmic bursting in the reticular thalamic nucleus (nRt), arising from interplay between Ca(v)3.3-type Ca(2+) channels and Ca(2+)-dependent small-conductance-type 2 (SK2) K(+) channels, underlies spindle generation. Correlative evidence indicates that spindles contribute to memory consolidation and protection against environmental noise in human NREMS. Here, we describe a molecular mechanism through which spindle power is selectively extended and we probed the actions of intensified spindling in the naturally sleeping mouse. Using electrophysiological recordings in acute brain slices from SK2 channel-overexpressing (SK2-OE) mice, we found that nRt bursting was potentiated and thalamic circuit oscillations were prolonged. Moreover, nRt cells showed greater resilience to transit from burst to tonic discharge in response to gradual depolarization, mimicking transitions out of NREMS. Compared with wild-type littermates, chronic EEG recordings of SK2-OE mice contained less fragmented NREMS, while the NREMS EEG power spectrum was conserved. Furthermore, EEG spindle activity was prolonged at NREMS exit. Finally, when exposed to white noise, SK2-OE mice needed stronger stimuli to arouse. Increased nRt bursting thus strengthens spindles and improves sleep quality through mechanisms independent of EEG slow waves (<4 Hz), suggesting SK2 signaling as a new potential therapeutic target for sleep disorders and for neuropsychiatric diseases accompanied by weakened sleep spindles.
authors.affiliation: Department of Fundamental Neuroscience, University of Lausanne, CH-1005 Lausanne, Switzerland.
authors.forename: Ralf D
authors.initials: RD
authors.lastname: Wimmer
authors.forename: Simone
authors.initials: S
authors.lastname: Astori
authors.forename: Chris T
authors.initials: CT
authors.lastname: Bond
authors.forename: Zita
authors.initials: Z
authors.lastname: Rovó
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Chatton
authors.forename: John P
authors.initials: JP
authors.lastname: Adelman
authors.forename: Paul
authors.initials: P
authors.lastname: Franken
authors.forename: Anita
authors.initials: A
authors.lastname: Lüthi
mesh_terms: D000200:Action Potentials; D000818:Animals; D001143:Arousal / Q000502:physiology*; D001309:Auditory Threshold; D002478:Cells, Cultured / Q000502:physiology; D004569:Electroencephalography; D005260:Female; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018408:Patch-Clamp Techniques; D017286:Polysomnography; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000502:physiology; D012894:Sleep Stages / Q000502:physiology*; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013047:Specific Pathogen-Free Organisms; D013787:Thalamic Nuclei / Q000166:cytology / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C496898:Kcnn2 protein, mouse; D011993:Recombinant Fusion Proteins; D051640:Small-Conductance Calcium-Activated Potassium Channels