Protein Kinase C Activity and Delayed Recovery of Sleep-Wake Cycle in Mouse Model of Bipolar Disorder

  • Moon, Eunsoo (Department of Psychiatry and Medical Research Institute, Pusan National University Hospital) ;
  • Choe, Byeong-Moo (Department of Psychiatry, Dong-A University School of Medicine) ;
  • Park, Je-Min (Department of Psychiatry and Medical Research Institute, Pusan National University Hospital) ;
  • Chung, Young In (Department of Psychiatry, Pusan National University School of Medicine) ;
  • Lee, Byung Dae (Department of Psychiatry and Medical Research Institute, Pusan National University Hospital) ;
  • Park, Jae-Hong (Department of Psychiatry, Dong-A University School of Medicine) ;
  • Lee, Young Min (Department of Psychiatry and Medical Research Institute, Pusan National University Hospital) ;
  • Jeong, Hee Jeong (Department of Psychiatry and Medical Research Institute, Pusan National University Hospital) ;
  • Cheon, YongJun (Department of Psychiatry, Dongrae Hospital) ;
  • Choi, Yoonmi (Department of Psychiatry and Medical Research Institute, Pusan National University Hospital) ;
  • Park, Jeonghyun (Department of Psychiatry and Medical Research Institute, Pusan National University Hospital)
  • Received : 2018.04.03
  • Accepted : 2018.05.23
  • Published : 2018.09.30


Objective Previous studies reported the delayed recovery group after circadian rhythm disruption in mice showed higher quinpirole-induced locomotor activity. This study aimed to compare not only Protein Kinase C (PKC) activities in frontal, striatal, hippocampus and cerebellum, but also relative PKC activity ratios among brain regions according to recovery of circadian rhythm. Methods The circadian rhythm disruption protocol was applied to eight-week-old twenty male Institute Cancer Research mice. The circadian rhythm recovery patterns were collected through motor activities measured by Mlog system. Depressive and manic proneness were examined by forced swim test and quinpirole-induced open field test respectively. Enzyme-linked immunosorbent assay was employed to measure PKC activities. Results The delayed recovery group presented greater locomotor activities than the early recovery group (p=0.033). The delayed recovery group had significantly lower frontal PKC activity than the other (p=0.041). The former showed lower frontal/cerebellar PKC activity ratio (p=0.047) but higher striatal/frontal (p=0.038) and hippocampal/frontal (p=0.007) PKC activities ratios than the latter. Conclusion These findings support potential mechanism of delayed recovery after circadian disruption in bipolar animal model could be an alteration of relative PKC activities among mood regulation related brain regions. It is required to investigate the PKC downstream signaling related to the delayed recovery pattern.


  1. Murray G, Harvey A. Circadian rhythms and sleep in bipolar disorder. Bipolar Disord 2010;12:459-472.
  2. Malkoff-Schwartz S, Frank E, Anderson B, Sherrill JT, Siegel L, Patterson D, et al. Stressful life events and social rhythm disruption in the onset of manic and depressive bipolar episodes: a preliminary investigation. Arch Gen Psychiatry 1998;55:702-707.
  3. Geoffroy PA, Scott J, Boudebesse C, Lajnef M, Henry C, Leboyer M, et al. Sleep in patients with remitted bipolar disorders: a meta-analysis of actigraphy studies. Acta Psychiatr Scand 2015;131:89-99.
  4. Serretti A, Benedetti F, Mandelli L, Lorenzi C, Pirovano A, Colombo C, et al. Genetic dissection of psychopathological symptoms: insomnia in mood disorders and CLOCK gene polymorphism. Am J Med Genet B Neuropsychiatr Genet 2003;121:35-38.
  5. Shi J, Wittke-Thompson JK, Badner JA, Hattori E, Potash JB, Willour VL, et al. Clock genes may influence bipolar disorder susceptibility and dysfunctional circadian rhythm. Am J Med Genet B Neuropsychiatr Genet 2008;147B:1047-1055.
  6. Friedman E, Hoau Yan W, Levinson D, Connell TA, Singh H. Altered platelet protein kinase C activity in bipolar affective disorder, manic episode. Biol Psychiatry 1993;33:520-525.
  7. Hahn CG, Umapathy, Wang HY, Koneru R, Levinson DF, Friedman E. Lithium and valproic acid treatments reduce PKC activation and receptor-G protein coupling in platelets of bipolar manic patients. J Psychiatr Res 2005;39:355-363.
  8. Wang HY, Friedman E. Enhanced protein kinase C activity and translocation in bipolar affective disorder brains. Biol Psychiatry 1996;40: 568-575.
  9. Wang HY, Markowitz P, Levinson D, Undie AS, Friedman E. Increased membrane-associated protein kinase C activity and translocation in blood platelets from bipolar affective disorder patients. J Psychiatr Res 1999;33:171-179.
  10. Abrial E, Lucas G, Scarna H, Haddjeri N, Lambas-Senas L. A role for the PKC signaling system in the pathophysiology and treatment of mood disorders: involvement of a functional imbalance? Mol Neurobiol 2011; 44:407-419.
  11. Nam HJ, Boo K, Kim D, Han DH, Choe HK, Kim CR, et al. Phosphorylation of LSD1 by PKCalpha is crucial for circadian rhythmicity and phase resetting. Mol Cell 2014;53:791-805.
  12. Lee B, Almad A, Butcher GQ, Obrietan K. Protein kinase C modulates the phase-delaying effects of light in the mammalian circadian clock. Eur J Neurosci 2007;26:451-462.
  13. Abrial E, Etievant A, Betry C, Scarna H, Lucas G, Haddjeri N, et al. Protein kinase C regulates mood-related behaviors and adult hippocampal cell proliferation in rats. Prog Neuropsychopharmacol Biol Psychiatry 2013;43:40-48.
  14. Kantor L, Gnegy ME. Protein kinase C inhibitors block amphetaminemediated dopamine release in rat striatal slices. J Pharmacol Exp Ther 1998;284:592-598.
  15. Szabo ST, Machado-Vieira R, Yuan P, Wang Y, Wei Y, Falke C, et al. Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania. Neuropharmacology 2009; 56:47-55.
  16. Jung SH, Park JM, Moon E, Chung YI, Lee BD, Lee YM, et al. Delay in the recovery of normal sleep-wake cycle after disruption of the lightdark cycle in mice:a bipolar disorder-prone animal model? Psychiatry Investig 2014;11:487-491.
  17. Kim SY, Moon E, Jeong HJ, Lee YM, Lee BD, Park JM. Delay in normalization of disrupted sleep-wake cycle in mice as a bipolar disorder-prone animal model (bipolar disorder-prone animal model). J Korean Neuropsychiatr Assoc 2016;55:209-214.
  18. Huang FL, Yoshida Y, Nakabayashi H, Huang KP. Differential distribution of protein kinase C isozymes in the various regions of brain. J Biol Chem 1987;262:15714-15720.
  19. Drevets WC. Neuroimaging studies of mood disorders. Biol Psychiatry 2000;48:813-829.
  20. Ji L, Chauhan A, Chauhan V. Reduced activity of protein kinase C in the frontal cortex of subjects with regressive autism: relationship with developmental abnormalities. Int J Biol Sci 2012;8:1075-1084.
  21. Jung MS, Lee YM, Moon E, Park JM. Prediction of Sleep-Awake State of Mouse by Mlog Locomotor Activity Analyzing System. Busan: Psychiatry, Pusan National University; 2015.
  22. Porsolt RD, Le Pichon M, Jalfre M. Depression: a new animal model sensitive to antidepressant treatments. Nature 1977;266:730-732.
  23. Can A, Dao DT, Arad M, Terrillion CE, Piantadosi SC, Gould TD. The mouse forced swim test. J Vis Exp 2012;(59):e3638.
  24. Castagne V, Porsolt RD, Moser P. Use of latency to immobility improves detection of antidepressant-like activity in the behavioral despair test in the mouse. Eur J Pharmacol 2009;616:128-133.
  25. Gessa GL, Pani L, Fadda P, Fratta W. Sleep deprivation in the rat: an animal model of mania. Eur Neuropsychopharmacol 1995;5 Suppl:89-93.
  26. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, Krishnan V, et al. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A 2007;104:6406-6411.
  27. Le-Niculescu H, McFarland MJ, Ogden CA, Balaraman Y, Patel S, Tan J, et al. Phenomic, convergent functional genomic, and biomarker studies in a stress-reactive genetic animal model of bipolar disorder and co-morbid alcoholism. Am J Med Genet B Neuropsychiatr Genet 2008; 147B:134-166.
  28. Molendijk ML, de Kloet ER. Immobility in the forced swim test is adaptive and does not reflect depression. Psychoneuroendocrinology 2015; 62:389-391.
  29. Kato T, Kasahara T, Kubota-Sakashita M, Kato TM, Nakajima K. Animal models of recurrent or bipolar depression. Neuroscience 2016;321: 189-196.
  30. Pandey GN, Ren X, Dwivedi Y, Pavuluri MN. Decreased protein kinase C (PKC) in platelets of pediatric bipolar patients: effect of treatment with mood stabilizing drugs. J Psychiatr Res 2008;42:106-116.
  31. Perlis RH, Miyahara S, Marangell LB, Wisniewski SR, Ostacher M, Del-Bello MP, et al. Long-term implications of early onset in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry 2004;55:875-881.
  32. Lofthouse N, Fristad M, Splaingard M, Kelleher K, Hayes J, Resko S. Web survey of sleep problems associated with early-onset bipolar spectrum disorders. J Pediatr Psychol 2008;33:349-357.
  33. Dilsaver SC, Akiskal HS. "Mixed hypomania" in children and adolescents: is it a pediatric bipolar phenotype with extreme diurnal variation between depression and hypomania? J Affect Disord 2009;116:12-17.
  34. Post RM, Leverich GS, Kupka RW, Keck PE Jr, McElroy SL, Altshuler LL, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry 2010;71:864-872.
  35. Rogers TD, Dickson PE, Heck DH, Goldowitz D, Mittleman G, Blaha CD. Connecting the dots of the cerebro-cerebellar role in cognitive function: neuronal pathways for cerebellar modulation of dopamine release in the prefrontal cortex. Synapse 2011;65:1204-1212.
  36. Berk M, Dodd S, Kauer-Sant'anna M, Malhi GS, Bourin M, Kapczinski F, et al. Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatr Scand Suppl 2007: 41-49.
  37. Strakowski SM, Delbello MP, Adler CM. The functional neuroanatomy of bipolar disorder: a review of neuroimaging findings. Mol Psychiatry 2005;10:105-116.
  38. Strakowski SM, Adler CM, Almeida J, Altshuler LL, Blumberg HP, Chang KD, et al. The functional neuroanatomy of bipolar disorder: a consensus model. Bipolar Disord 2012;14:313-325.
  39. Ring HA, Serra-Mestres J. Neuropsychiatry of the basal ganglia. J Neurol Neurosurg Psychiatry 2002;72:12-21.
  40. Wessa M, Linke J. Emotional processing in bipolar disorder: behavioural and neuroimaging findings. Int Rev Psychiatry 2009;21:357-367.
  41. Gabriel LR, Wu S, Kearney P, Bellve KD, Standley C, Fogarty KE, et al. Dopamine transporter endocytic trafficking in striatal dopaminergic neurons: differential dependence on dynamin and the actin cytoskeleton. J Neurosci 2013;33:17836-17846.
  42. Nogues X, Micheau J, Jaffard R. Protein kinase C activity in the hippocampus following spatial learning tasks in mice. Hippocampus 1994; 4:71-77.
  43. Vazquez SI, Vazquez A, Pena de Ortiz S. Different hippocampal activity profiles for PKA and PKC in spatial discrimination learning. Behav Neurosci 2000;114:1109-1118.
  44. Goldapple K, Segal Z, Garson C, Lau M, Bieling P, Kennedy S, et al. Modulation of cortical-limbic pathways in major depression: treatment-specific effects of cognitive behavior therapy. Arch Gen Psychiatry 2004; 61:34-41.
  45. Caetano SC, Olvera RL, Glahn D, Fonseca M, Pliszka S, Soares JC. Fronto-limbic brain abnormalities in juvenile onset bipolar disorder. Biol Psychiatry 2005;58:525-531.
  46. Marchand WR, Bennett PJ, Dilda DS. Evidence for frontal-subcortical circuit abnormalities in bipolar affective disorder. Psychiatry (Edgmont) 2005;2:26-33.