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

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 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. 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 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. Conclusions The 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.

[1]  F. Dickerson,et al.  Antibodies to the glutamate receptor in mania , 2012, Bipolar disorders.

[2]  Ellen Frank,et al.  Interpersonal and social rhythm therapy: managing the chaos of bipolar disorder , 2000, Biological Psychiatry.

[3]  Fred W. Turek,et al.  Obesity and Metabolic Syndrome in Circadian Clock Mutant Mice , 2005, Science.

[4]  S. Potkin,et al.  Rapid and Sustained Antidepressant Response with Sleep Deprivation and Chronotherapy in Bipolar Disorder , 2009, Biological Psychiatry.

[5]  Mohamad A Mikati,et al.  Distinct neurological disorders with ATP1A3 mutations , 2014, The Lancet Neurology.

[6]  Warren Ladiges,et al.  Voluntary Wheel Running in Mice , 2015, Current protocols in mouse biology.

[7]  Syed M. Adil,et al.  Knock‐in mouse model of alternating hemiplegia of childhood: Behavioral and electrophysiologic characterization , 2015, Epilepsia.

[8]  Christopher Lawrence,et al.  DEGENERATION , 2020, Side Effects May Include Strangers.

[9]  M. Hagiwara,et al.  Na, K-ATPase α3 is a death target of Alzheimer patient amyloid-β assembly , 2015, Proceedings of the National Academy of Sciences.

[10]  B. Hamre,et al.  Blocking blue light during mania – markedly increased regularity of sleep and rapid improvement of symptoms: a case report , 2014, Bipolar disorders.

[11]  D. Bechtold,et al.  Acute Suppressive and Long-Term Phase Modulation Actions of Orexin on the Mammalian Circadian Clock , 2014, The Journal of Neuroscience.

[12]  Corinne Jud,et al.  A guideline for analyzing circadian wheel-running behavior in rodents under different lighting conditions , 2005, Biological Procedures Online.

[13]  H. Piggins,et al.  Spatiotemporal Heterogeneity in the Electrical Activity of Suprachiasmatic Nuclei Neurons and their Response to Photoperiod , 2009, Journal of biological rhythms.

[14]  Ueli Schibler,et al.  The Orphan Nuclear Receptor REV-ERBα Controls Circadian Transcription within the Positive Limb of the Mammalian Circadian Oscillator , 2002, Cell.

[15]  R. Ebstein,et al.  Association Between Sodium- and Potassium-Activated Adenosine Triphosphatase α Isoforms and Bipolar Disorders , 2009, Biological Psychiatry.

[16]  Steven H. Jones,et al.  Actigraphic assessment of circadian activity and sleep patterns in bipolar disorder. , 2005, Bipolar disorders.

[17]  C. Colwell,et al.  Excitatory mechanisms in the suprachiasmatic nucleus: the role of AMPA/KA glutamate receptors. , 2002, Journal of neurophysiology.

[18]  David K Welsh,et al.  Suprachiasmatic nucleus: cell autonomy and network properties. , 2010, Annual review of physiology.

[19]  F. Benedetti,et al.  Chronobiology of Bipolar Disorder: Therapeutic Implication , 2015, Current Psychiatry Reports.

[20]  N. Mrosovsky,et al.  Classical and melanopsin photoreception in irradiance detection: negative masking of locomotor activity by light , 2008, The European journal of neuroscience.

[21]  K. Sweadner,et al.  Cellular and Subcellular Specification of Na,K-ATPase α and β Isoforms in the Postnatal Development of Mouse Retina , 1999, The Journal of Neuroscience.

[22]  H. Piggins,et al.  Behavioral Responses of Vipr2–/– Mice to Light , 2008, Journal of biological rhythms.

[23]  L. Knorring.  Visual averaged evoked responses in patients with bipolar affective disorders. , 1978 .

[24]  Nicolas Fritz,et al.  α‐synuclein assemblies sequester neuronal α3‐Na+/K+‐ATPase and impair Na+ gradient , 2015, The EMBO journal.

[25]  Ueli Schibler,et al.  Crosstalk between components of circadian and metabolic cycles in mammals. , 2011, Cell metabolism.

[26]  H. Okamura,et al.  Activation of AMPA Receptors in the Suprachiasmatic Nucleus Phase-Shifts the Mouse Circadian Clock In Vivo and In Vitro , 2010, PloS one.

[27]  Céline Vetter,et al.  Social jetlag and obesity. , 2012, Current biology : CB.

[28]  D. Golombek,et al.  Physiology of circadian entrainment. , 2010, Physiological reviews.

[29]  J. Storm-Mathisen,et al.  Glutamate‐like Immunoreactivity in Retinal Terminals of the Mouse Suprachiasmatic Nucleus , 1993, The European journal of neuroscience.

[30]  R. Porter,et al.  Effect of transmeridian travel and jetlag on mood disorders: Evidence and implications , 2016, The Australian and New Zealand journal of psychiatry.

[31]  M. Vansteensel,et al.  Seasonal Encoding by the Circadian Pacemaker of the SCN , 2007, Current Biology.

[32]  P. Gallagher,et al.  Sleep and circadian rhythm disturbance in bipolar disorder , 2017, Psychological Medicine.

[33]  F. Bellivier,et al.  Seasonality and bipolar disorder: a systematic review, from admission rates to seasonality of symptoms. , 2014, Journal of affective disorders.

[34]  M. Cuttle,et al.  Mechanisms of neuronal hyperexcitability caused by partial inhibition of Na+-K+-ATPases in the rat CA1 hippocampal region. , 2002, Journal of neurophysiology.

[35]  T. Takumi,et al.  Constant light enhances synchrony among circadian clock cells and promotes behavioral rhythms in VPAC2-signaling deficient mice , 2015, Scientific Reports.

[36]  C. Pennartz,et al.  Electrophysiological and morphological heterogeneity of neurons in slices of rat suprachiasmatic nucleus , 1998, The Journal of physiology.

[37]  Aleksandar Videnovic,et al.  Circadian and sleep disorders in Parkinson's disease , 2013, Experimental Neurology.

[38]  O. Çalıyurt,et al.  Resting energy expenditure in manic episode. , 2009, Bipolar disorders.

[39]  Jong-Woo Sohn.  Network of hypothalamic neurons that control appetite , 2015, BMB reports.

[40]  A. Stoll,et al.  Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder , 2004, Biological Psychiatry.

[41]  D. Bechtold,et al.  Suppressed cellular oscillations in after-hours mutant mice are associated with enhanced circadian phase-resetting , 2012, The Journal of physiology.

[42]  M. Dobretsov,et al.  Neuronal function and alpha3 isoform of the Na/K-ATPase. , 2005, Frontiers in bioscience : a journal and virtual library.

[43]  H. Brismar,et al.  A specific and essential role for Na,K-ATPase alpha 3 in neurons co-expressing alpha 1 and alpha 3 , 2013 .

[44]  J. Takahashi,et al.  Molecular architecture of the mammalian circadian clock. , 2014, Trends in cell biology.

[45]  P. Nissen,et al.  Distribution of Na/K‐ATPase alpha 3 isoform, a sodium‐potassium P‐type pump associated with rapid‐onset of dystonia parkinsonism (RDP) in the adult mouse brain , 2011, The Journal of comparative neurology.

[46]  H. Piggins,et al.  A riot of rhythms: neuronal and glial circadian oscillators in the mediobasal hypothalamus , 2009, Molecular Brain.

[47]  S. Yamazaki,et al.  Masking Responses to Light in Period Mutant Mice , 2011, Chronobiology international.

[48]  M. Leboyer,et al.  Genetics of circadian rhythms and mood spectrum disorders , 2011, European Neuropsychopharmacology.

[49]  Kwoon Y. Wong,et al.  Photoresponse diversity among the five types of intrinsically photosensitive retinal ganglion cells , 2014, The Journal of physiology.

[50]  Samer Hattar,et al.  Light as a central modulator of circadian rhythms, sleep and affect , 2014, Nature Reviews Neuroscience.

[51]  I. Soreca.  Circadian rhythms and sleep in bipolar disorder: implications for pathophysiology and treatment , 2014, Current opinion in psychiatry.

[52]  Anne-Marie Chang,et al.  The mouse Clock mutation reduces circadian pacemaker amplitude and enhances efficacy of resetting stimuli and phase-response curve amplitude. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[53]  H. Piggins,et al.  Electrophysiology of the suprachiasmatic circadian clock , 2007, Progress in Neurobiology.

[54]  F. Benedetti,et al.  Chronobiological Therapy for Mood Disorders , 2015, Current Psychiatry Reports.

[55]  Trevor R. Norman,et al.  Effect of Sodium Valproate on Nocturnal Melatonin Sensitivity to Light in Healthy Volunteers , 2005, Neuropsychopharmacology.

[56]  M. Stacy,et al.  Psychiatric disorders in rapid-onset dystonia-parkinsonism , 2012, Neurology.

[57]  Hendrik Rosewich,et al.  A novel ATP1A3 mutation with unique clinical presentation , 2014, Journal of the Neurological Sciences.

[58]  D. Bechtold,et al.  Metabolic rhythm abnormalities in mice lacking VIP-VPAC2 signaling. , 2008, American journal of physiology. Regulatory, integrative and comparative physiology.

[59]  Sooyoung Chung,et al.  Impact of Circadian Nuclear Receptor REV-ERBα on Midbrain Dopamine Production and Mood Regulation , 2014, Cell.

[60]  J. Nyengaard,et al.  Cognitive deficits caused by a disease-mutation in the α3 Na+/K+-ATPase isoform , 2016, Scientific Reports.

[61]  E. Musiek.  Circadian clock disruption in neurodegenerative diseases: cause and effect? , 2015, Front. Pharmacol..

[62]  Daniel B. Forger,et al.  Daily Electrical Silencing in the Mammalian Circadian Clock , 2009, Science.

[63]  Christophe D. Proulx,et al.  Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice , 2016, Biological Psychiatry.

[64]  R. Foster,et al.  Sleep and circadian rhythm disruption in psychiatric and neurodegenerative disease , 2010, Nature Reviews Neuroscience.

[65]  Tomoko Yoshikawa,et al.  Retinal pathways influence temporal niche , 2008, Proceedings of the National Academy of Sciences.

[66]  J. Os,et al.  The size and burden of mental disorders and other disorders of the brain in Europe 2010 , 2011, European Neuropsychopharmacology.

[67]  H. Brismar,et al.  A Specific and Essential Role for Na,K-ATPase α3 in Neurons Co-expressing α1 and α3* , 2012, The Journal of Biological Chemistry.

[68]  J. Roder,et al.  Attenuation of mania-like behavior in Na+,K+-ATPase α3 mutant mice by prospective therapies for bipolar disorder: Melatonin and exercise , 2014, Neuroscience.

[69]  T. Horvath,et al.  Metabolism and Mental Illness. , 2016, Trends in molecular medicine.

[70]  S. Angers,et al.  Glutamate Transporter Coupling to Na,K-ATPase , 2009, The Journal of Neuroscience.

[71]  K. Deisseroth,et al.  Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice , 2014, Molecular Psychiatry.

[72]  C. Colwell.  Linking neural activity and molecular oscillations in the SCN , 2011, Nature Reviews Neuroscience.

[73]  Ook Joon Yoo,et al.  PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[74]  D. Kupfer,et al.  Bipolar disorder diagnosis: challenges and future directions , 2013, The Lancet.

[75]  Rong-Chi Huang,et al.  Effects of sodium pump activity on spontaneous firing in neurons of the rat suprachiasmatic nucleus. , 2006, Journal of neurophysiology.

[76]  Paul D. Gamlin,et al.  Measuring and using light in the melanopsin age , 2014, Trends in Neurosciences.

[77]  F. Davis,et al.  Disruption of masking by hypothalamic lesions in Syrian hamsters , 2004, Journal of Comparative Physiology A.

[78]  Joanna Mattis,et al.  Circadian Rhythms, Sleep, and Disorders of Aging , 2016, Trends in Endocrinology & Metabolism.

[79]  C. McClung,et al.  Animal models of bipolar mania: The past, present and future , 2016, Neuroscience.

[80]  T. Tcheng,et al.  Intrinsic neuronal rhythms in the suprachiasmatic nuclei and their adjustment. , 1995, Ciba Foundation symposium.

[81]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[82]  H. Kori,et al.  Mice Genetically Deficient in Vasopressin V1a and V1b Receptors Are Resistant to Jet Lag , 2013, Science.

[83]  R. Wyatt,et al.  The Na,K-ATPase hypothesis for bipolar illness , 1995, Biological Psychiatry.

[84]  Bart P C van de Warrenburg,et al.  The Genetic Homogeneity of CAPOS Syndrome: Four New Patients With the c.2452G>A (p.Glu818Lys) Mutation in the ATP1A3 Gene. , 2016, Pediatric neurology.

[85]  M. McCarthy,et al.  Circadian Clock and Stress Interactions in the Molecular Biology of Psychiatric Disorders , 2014, Current Psychiatry Reports.

[86]  Baowu Wang,et al.  Evidence for Seasonal Mania: A Review , 2013, Journal of psychiatric practice.

[87]  M. Bucan,et al.  Assessment of circadian function in fibroblasts of patients with bipolar disorder , 2009, Molecular Psychiatry.

[88]  H. Piggins,et al.  Circadian and dark-pulse activation of orexin/hypocretin neurons , 2008, Molecular Brain.

[89]  Kamran Khodakhah,et al.  Abnormal High-Frequency Burst Firing of Cerebellar Neurons in Rapid-Onset Dystonia-Parkinsonism , 2014, The Journal of Neuroscience.

[90]  A. Carvalho,et al.  Genetic Studies on the Tripartite Glutamate Synapse in the Pathophysiology and Therapeutics of Mood Disorders , 2017, Neuropsychopharmacology.

[91]  Glutamatergic effects of divalproex in adolescents with mania: a proton magnetic resonance spectroscopy study. , 2012, Journal of the American Academy of Child and Adolescent Psychiatry.

[92]  K. Sweadner,et al.  Two different Na,K-ATPases in the optic nerve: cells of origin and axonal transport. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[93]  L. Brown,et al.  The CRTC1-SIK1 Pathway Regulates Entrainment of the Circadian Clock , 2013, Cell.

[94]  Meghan C Towne,et al.  A novel de novo mutation in ATP1A3 and childhood-onset schizophrenia , 2016, Cold Spring Harbor molecular case studies.

[95]  Shin Yamazaki,et al.  Constant light desynchronizes mammalian clock neurons , 2005, Nature Neuroscience.

[96]  P. Grof,et al.  Effect of chronic lithium on sensitivity to light in male and female bipolar patients , 1989, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[97]  Kole T. Roybal,et al.  Mania-like behavior induced by disruption of CLOCK , 2007, Proceedings of the National Academy of Sciences.

[98]  L. F. Abbott,et al.  A Computational Model of Motor Neuron Degeneration , 2014, Neuron.