title: The Circadian Clock Gene Period1 Connects the Molecular Clock to Neural Activity in the Suprachiasmatic Nucleus.
abstract: The neural activity patterns of suprachiasmatic nucleus (SCN) neurons are dynamically regulated throughout the circadian cycle with highest levels of spontaneous action potentials during the day. These rhythms in electrical activity are critical for the function of the circadian timing system and yet the mechanisms by which the molecular clockwork drives changes in the membrane are not well understood. In this study, we sought to examine how the clock gene Period1 (Per1) regulates the electrical activity in the mouse SCN by transiently and selectively decreasing levels of PER1 through use of an antisense oligodeoxynucleotide. We found that this treatment effectively reduced SCN neural activity. Direct current injection to restore the normal membrane potential partially, but not completely, returned firing rate to normal levels. The antisense treatment also reduced baseline [Ca(2+)]i levels as measured by Fura2 imaging technique. Whole cell patch clamp recording techniques were used to examine which specific potassium currents were altered by the treatment. These recordings revealed that the large conductance [Ca(2+)]i-activated potassium currents were reduced in antisense-treated neurons and that blocking this current mimicked the effects of the anti-sense on SCN firing rate. These results indicate that the circadian clock gene Per1 alters firing rate in SCN neurons and raise the possibility that the large conductance [Ca(2+)]i-activated channel is one of the targets.
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA tkudo3@gmail.com.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
authors.forename: Gene D
authors.initials: GD
authors.lastname: Block
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Colwell
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D002413:Cations, Divalent / Q000378:metabolism; D057906:Circadian Clocks / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D055879:Gene Knock-In Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D056950:Period Circadian Proteins / Q000235:genetics / Q000378:metabolism*; D013493:Suprachiasmatic Nucleus / Q000187:drug effects / Q000502:physiology*; D046509:Tissue Culture Techniques
chemical_list: D002413:Cations, Divalent; D051036:Large-Conductance Calcium-Activated Potassium Channels; C539023:Per1 protein, mouse; C513312:Per2 protein, mouse; D056950:Period Circadian Proteins; D002118:Calcium
keywords: BK currents; Per1; calcium; circadian