Circadian Disruptions in the Myshkin Mouse Model of Mania are Independent of Deficits in Suprachiasmatic Molecular Clock Function

Joseph Timothy, Natasza Klas, Harshmeena Sanghani, Taghreed Al-Mansouri, Alun Hughes, Greer S Kirshenbaum, Vincent Brienza, Mino Belle, Martin R Ralph, Steven J. Clapcote, Hugh Piggins

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Alterations in environmental light and intrinsic circadian function
have strong associations with mood disorders. The neural origins underpinning these changes remain unclear, although genetic deficits in the molecular clock regularly render mice with altered mood-associated phenotypes.
METHODS: A detailed circadian and light-associated behavioral characterization of the Na+/K+-ATPase (NKA) α3 Myshkin (Myk/+) mouse model of mania was
performed. NKA α3 does not reside within the core circadian molecular clockwork, but Myk/+ mice exhibit concomitant disruption in circadian rhythms and mood. The neural basis of this phenotype was investigated through molecular and electrophysiological dissection of the master circadian pacemaker, the suprachiasmatic nuclei (SCN). Light input and glutamatergic signalling to the SCN were concomitantly assessed through behavioral assays and calcium imaging.
RESULTS: In vivo assays revealed several circadian abnormalities including
lengthened period and instability of behavioral rhythms, and elevated metabolic rate. Grossly aberrant responses to light included accentuated resetting, accelerated reentrainment and an absence of locomotor suppression. Bioluminescent recording of circadian clock protein (PER2) output from ex vivo SCN revealed no deficits in Myk/+ molecular clock function. Optic-nerve crush rescued the circadian period of Myk/+ behavior, highlighting that afferent inputs are critical upstream mediators. Electrophysiological and calcium imaging SCN recordings demonstrated changes in response to glutamatergic stimulation as well as electrical output indicative of altered retinal input processing.
CONCLUSIONS: The Myshkin model demonstrates profound circadian and lightresponsive behavioral alterations independent of molecular clock disruption. Afferent light-signaling drives behavioral changes and raises new mechanistic implications for circadian disruption in affective disorders.
Original languageEnglish
Pages (from-to)827-837
JournalBiological Psychiatry
Issue number11
Early online date20 May 2017
Publication statusPublished - 20 May 2017


  • Bipolar
  • Circadian
  • Light
  • Mania
  • Mood
  • Suprachiasmatic


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