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

Abstract

BackgroundAlterations 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.MethodsA detailed circadian and light-associated behavioral characterization of the Na+/K+-ATPase α3 Myshkin (Myk/+) mouse model of mania was performed. Na+/K+-ATPase 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 signaling to the SCN were concomitantly assessed through behavioral assays and calcium imaging.ResultsIn 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 re-entrainment, and an absence of locomotor suppression. Bioluminescent recording of circadian clock protein (PERIOD2) 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 the response to glutamatergic stimulation as well as the electrical output indicative of altered retinal input processing.ConclusionsThe Myshkin model demonstrates profound circadian and light-responsive behavioral alterations independent of molecular clock disruption. Afferent light signaling drives behavioral changes and raises new mechanistic implications for circadian disruption in affective disorders.

Perspectives in affective disorders: Clocks and sleep

“…There are very few polymorphisms, such as the CLOCK ‐3111 T/C, which have been both studied in humans and modelled in animals to elucidate their neurobiological effects (Ozburn et al., ). A continuously evolving behavioural modelling of clock gene mutations in animals allows to deepen insights on the role of the molecular clock machinery in mammalian brain functioning (Parekh et al., ; Timothy et al., ), but this kind of evidence has not yet been matched with results of large genomewide association studies (GWAS) in mood disorders (McCarthy, ). Replication of single gene effects in humans, and modelling in animals, is needed before the clinical relevance of these gene variants can be assessed and possibly translated into clinical psychiatric practice, also anticipating the need for reverse‐translational and reverse‐phenotyping approaches to identify the role of single gene variants across current psychiatric illness categories (Demkow & Wolanczyk, ).…”

Circadian Rhythm Disturbances in Mood Disorders: Insights into the Role of the Suprachiasmatic Nucleus

“…Since Atp1a3 is expressed in the SCN and circadian rhythm disturbances frequently occur in mania, Timothy and colleagues looked at the wheel-running rhythms of Myk /+ mice [ 332 ]. Myk /+ mice had longer wheel-running periods and active phases.…”

Dysfunction of ventral tegmental area GABA neurons causes mania-like behavior

“…In mice, pathological hyperactivity and elevated mood can be generated by various gene mutations and deletions: e.g. ClockD19 6 , REV-erba 7 , ErbB4 tyrosine kinase deletion in noradrenergic locus ceruleus cells 8 , GSK-3b overexpression 9 , dopamine transporter knockdown 10,11 , SHANK2 knockout 12 , SHANK3 overexpression 13 , ANK3 disruptions 14 , ionotropic glutamate/AMPA receptor GluR1 knockout 15 , ionotropic glutamate/kainate GluR6 knockout 16 , phospholipase cg1 8 , glutamate-cysteine ligase modifier unit knockout 17 , and the Na/K-ATPase a3 Myshkin (Myk/+) mutation [18][19][20] . Some of these gene manipulations alter excitation-inhibition (E-I) balance 8,13,15,16,21 , and/or elevate catecholamines 6-8, 10, 22 , suggesting common themes that could underlie the emergence of some types of mania.…”