Protein kinase Mζ in medial prefrontal cortex mediates depressive-like behavior and antidepressant response

A Correction to this article was published on 13 March 2019

This article has been updated

Abstract

Neuronal atrophy and alterations of synaptic structure and function in the medial prefrontal cortex (mPFC) have been implicated in the pathogenesis of depression, but the underlying molecular mechanisms are largely unknown. The protein kinase Mζ (PKMζ), a brain-specific atypical protein kinase C isoform, is important for maintaining long-term potentiation and storing memory. In the present study, we explored the role of PKMζ in mPFC in two rat models of depression, chronic unpredictable stress (CUS) and learned helplessness. The involvement of PKMζ in the antidepressant effects of conventional antidepressants and ketamine were also investigated. We found that chronic stress decreased the expression of PKMζ in the mPFC and hippocampus but not in the orbitofrontal cortex. Overexpression of PKMζ in mPFC prevented the depressive-like and anxiety-like behaviors induced by CUS, and reversed helplessness behaviors. Inhibition of PKMζ in mPFC by expressing a PKMζ dominant-negative mutant induced depressive-like behaviors after subthreshold unpredictable stress and increased learned helplessness behavior. Furthermore, stress-induced deficits in synaptic proteins and decreases in dendritic density and the frequency of miniature excitatory postsynaptic currents in the mPFC were prevented by PKMζ overexpression and potentiated by PKMζ inhibition in subthreshold stress rats. The antidepressants fluoxetine, desipramine and ketamine increased PKMζ expression in mPFC and PKMζ mediated the antidepressant effects of ketamine. These findings identify PKMζ in mPFC as a critical mediator of depressive-like behavior and antidepressant response, providing a potential therapeutic target in developing novel antidepressants.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Change history

References

  1. 1

    Kessler RC, Wang PS. The descriptive epidemiology of commonly occurring mental disorders in the United States. Annu Rev Public Health 2008; 29: 115–129.

    PubMed  Google Scholar 

  2. 2

    Mata DA, Ramos MA, Bansal N, Khan R, Guille C, Di Angelantonio E et al. Prevalence of depression and depressive symptoms among resident physicians: a systematic review and meta-analysis. JAMA 2015; 314: 2373–2383.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Lopez AD, Mathers CD. Measuring the global burden of disease and epidemiological transitions: 2002-2030. Ann Trop Med Parasitol 2006; 100: 481–499.

    CAS  PubMed  Google Scholar 

  4. 4

    Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med 2006; 354: 1243–1252.

    CAS  PubMed  Google Scholar 

  5. 5

    Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression. J Neurosci 1992; 12: 3628–3641.

    CAS  PubMed  Google Scholar 

  6. 6

    Baxter LR Jr, Schwartz JM, Phelps ME, Mazziotta JC, Guze BH, Selin CE et al. Reduction of prefrontal cortex glucose metabolism common to three types of depression. Arch Gen Psychiatry 1989; 46: 243–250.

    CAS  PubMed  Google Scholar 

  7. 7

    Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW et al. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 2012; 13: 769–787.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Keding TJ, Herringa RJ. Abnormal structure of fear circuitry in pediatric post-traumatic stress disorder. Neuropsychopharmacology 2015; 40: 537–545.

    PubMed  Google Scholar 

  9. 9

    Cook SC, Wellman CL. Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol 2004; 60: 236–248.

    PubMed  Google Scholar 

  10. 10

    Wellman CL. Dendritic reorganization in pyramidal neurons in medial prefrontal cortex after chronic corticosterone administration. J Neurobiol 2001; 49: 245–253.

    CAS  PubMed  Google Scholar 

  11. 11

    Martin KP, Wellman CL. NMDA receptor blockade alters stress-induced dendritic remodeling in medial prefrontal cortex. Cereb Cortex 2011; 21: 2366–2373.

    PubMed  PubMed Central  Google Scholar 

  12. 12

    Gourley SL, Kedves AT, Olausson P, Taylor JR. A history of corticosterone exposure regulates fear extinction and cortical NR2B, GluR2/3, and BDNF. Neuropsychopharmacology 2009; 34: 707–716.

    CAS  PubMed  Google Scholar 

  13. 13

    Li N, Liu RJ, Dwyer JM, Banasr M, Lee B, Son H et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry 2011; 69: 754–761.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Marsden WN. Synaptic plasticity in depression: molecular, cellular and functional correlates. Prog Neuropsychopharmacol Biol Psychiatry 2013; 43: 168–184.

    CAS  PubMed  Google Scholar 

  15. 15

    Quan MN, Zhang N, Wang YY, Zhang T, Yang Z. Possible antidepressant effects and mechanisms of memantine in behaviors and synaptic plasticity of a depression rat model. Neuroscience 2011; 182: 88–97.

    CAS  PubMed  Google Scholar 

  16. 16

    Dupin N, Mailliet F, Rocher C, Kessal K, Spedding M, Jay TM. Common efficacy of psychotropic drugs in restoring stress-induced impairment of prefrontal plasticity. Neurotox Res 2006; 10: 193–198.

    CAS  PubMed  Google Scholar 

  17. 17

    Qi H, Mailliet F, Spedding M, Rocher C, Zhang X, Delagrange P et al. Antidepressants reverse the attenuation of the neurotrophic MEK/MAPK cascade in frontal cortex by elevated platform stress; reversal of effects on LTP is associated with GluA1 phosphorylation. Neuropharmacology 2009; 56: 37–46.

    CAS  PubMed  Google Scholar 

  18. 18

    Hernandez AI, Blace N, Crary JF, Serrano PA, Leitges M, Libien JM et al. Protein kinase M zeta synthesis from a brain mRNA encoding an independent protein kinase C zeta catalytic domain. Implications for the molecular mechanism of memory. J Biol Chem 2003; 278: 40305–40316.

    CAS  PubMed  Google Scholar 

  19. 19

    Sajikumar S, Navakkode S, Sacktor TC, Frey JU. Synaptic tagging and cross-tagging: the role of protein kinase Mzeta in maintaining long-term potentiation but not long-term depression. J Neurosci 2005; 25: 5750–5756.

    CAS  PubMed  Google Scholar 

  20. 20

    Hrabetova S, Sacktor TC. Bidirectional regulation of protein kinase M zeta in the maintenance of long-term potentiation and long-term depression. J Neurosci 1996; 16: 5324–5333.

    CAS  PubMed  Google Scholar 

  21. 21

    Osten P, Valsamis L, Harris A, Sacktor TC. Protein synthesis-dependent formation of protein kinase Mzeta in long-term potentiation. J Neurosci 1996; 16: 2444–2451.

    CAS  PubMed  Google Scholar 

  22. 22

    Pastalkova E, Serrano P, Pinkhasova D, Wallace E, Fenton AA, Sacktor TC. Storage of spatial information by the maintenance mechanism of LTP. Science 2006; 313: 1141–1144.

    CAS  PubMed  Google Scholar 

  23. 23

    Shema R, Sacktor TC, Dudai Y. Rapid erasure of long-term memory associations in the cortex by an inhibitor of PKM zeta. Science 2007; 317: 951–953.

    CAS  PubMed  Google Scholar 

  24. 24

    Serrano P, Friedman EL, Kenney J, Taubenfeld SM, Zimmerman JM, Hanna J et al. PKMzeta maintains spatial, instrumental, and classically conditioned long-term memories. PLoS Biol 2008; 6: 2698–2706.

    CAS  PubMed  Google Scholar 

  25. 25

    Shema R, Haramati S, Ron S, Hazvi S, Chen A, Sacktor TC et al. Enhancement of consolidated long-term memory by overexpression of protein kinase Mzeta in the neocortex. Science 2011; 331: 1207–1210.

    CAS  PubMed  Google Scholar 

  26. 26

    Kandaswamy R, McQuillin A, Curtis D, Gurling H. Tests of linkage and allelic association between markers in the 1p36 PRKCZ (protein kinase C zeta) gene region and bipolar affective disorder. Am J Med Genet B Neuropsychiatr Genet 2012; 159B: 201–209.

    PubMed  Google Scholar 

  27. 27

    Zanca RM, Braren SH, Maloney B, Schrott LM, Luine VN, Serrano PA. Environmental enrichment increases glucocorticoid receptors and decreases GluA2 and protein kinase M zeta (PKMzeta) trafficking during chronic stress: a protective mechanism? Front Behav Neurosci 2015; 9: 303.

    PubMed  PubMed Central  Google Scholar 

  28. 28

    Ji LL, Tong L, Xu BK, Fu CH, Shu W, Peng JB et al. Intra-hippocampal administration of ZIP alleviates depressive and anxiety-like responses in an animal model of posttraumatic stress disorder. Behav Brain Funct 2014; 10: 28.

    PubMed  PubMed Central  Google Scholar 

  29. 29

    Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL. PKM-zeta is not required for hippocampal synaptic plasticity, learning and memory. Nature 2013; 493: 420–423.

    CAS  PubMed  Google Scholar 

  30. 30

    Lee AM, Kanter BR, Wang D, Lim JP, Zou ME, Qiu C et al. Prkcz null mice show normal learning and memory. Nature 2013; 493: 416–419.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    LeBlancq MJ, McKinney TL, Dickson CT. ZIP it: neural silencing is an additional effect of the PKM-zeta inhibitor zeta-inhibitory peptide. J Neurosci 2016; 36: 6193–6198.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 5 edn. Elsevier Academic Press: Amsterdam, 2005.

  33. 33

    Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 2010; 329: 959–964.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Li SX, Han Y, Xu LZ, Yuan K, Zhang RX, Sun CY et al. Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects. Mol Psychiatry 2017 doi: 10.1038/mp.2017.85.

    PubMed  PubMed Central  Google Scholar 

  35. 35

    Han Y, Luo Y, Sun J, Ding Z, Liu J, Yan W et al. AMPK signaling in the dorsal hippocampus negatively regulates contextual fear memory formation. Neuropsychopharmacology 2016; 41: 1849–1864.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Zhu WL, Shi HS, Wang SJ, Xu CM, Jiang WG, Wang X et al. Increased Cdk5/p35 activity in the dentate gyrus mediates depressive-like behaviour in rats. Int J Neuropsychopharmacol 2012; 15: 795–809.

    CAS  PubMed  Google Scholar 

  37. 37

    Xue YX, Zhu ZZ, Han HB, Liu JF, Meng SQ, Chen C et al. Overexpression of protein kinase Mzeta in the prelimbic cortex enhances the formation of long-term fear memory. Neuropsychopharmacology 2015; 40: 2146–2156.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Chen C, Meng SQ, Xue YX, Han Y, Sun CY, Deng JH et al. Epigenetic modification of PKMzeta rescues aging-related cognitive impairment. Sci Rep 2016; 6: 22096.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    Suo L, Zhao L, Si J, Liu J, Zhu W, Chai B et al. Predictable chronic mild stress in adolescence increases resilience in adulthood. Neuropsychopharmacology 2013; 38: 1387–1400.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Xue YX, Luo YX, Wu P, Shi HS, Xue LF, Chen C et al. A memory retrieval-extinction procedure to prevent drug craving and relapse. Science 2012; 336: 241–245.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Soztutar E, Colak E, Ulupinar E. Gender- and anxiety level-dependent effects of perinatal stress exposure on medial prefrontal cortex. Exp Neurol 2016; 275(Pt 2): 274–284.

    PubMed  Google Scholar 

  42. 42

    Holtmaat A, Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci 2009; 10: 647–658.

    CAS  PubMed  Google Scholar 

  43. 43

    Zhang W, Daly KM, Liang B, Zhang L, Li X, Li Y et al. BDNF rescues prefrontal dysfunction elicited by pyramidal neuron-specific DTNBP1 deletion in vivo. J Mol Cell Biol 2017; 9: 117–131.

    CAS  PubMed  Google Scholar 

  44. 44

    Zhang W, Zhang L, Liang B, Schroeder D, Zhang ZW, Cox GA et al. Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders. Nat Neurosci 2016; 19: 557–559.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Shao CY, Sondhi R, van de Nes PS, Sacktor TC. PKMzeta is necessary and sufficient for synaptic clustering of PSD-95. Hippocampus 2012; 22: 1501–1507.

    CAS  PubMed  Google Scholar 

  46. 46

    Bondi CO, Rodriguez G, Gould GG, Frazer A, Morilak DA. Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology 2008; 33: 320–331.

    CAS  PubMed  Google Scholar 

  47. 47

    Vialou V, Robison AJ, Laplant QC, Covington HE 3rd, Dietz DM, Ohnishi YN et al. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci 2010; 13: 745–752.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48

    Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 2000; 47: 351–354.

    CAS  PubMed  Google Scholar 

  49. 49

    Schuette SR, Fernandez-Fernandez D, Lamla T, Rosenbrock H, Hobson S. Overexpression of protein kinase Mzeta in the hippocampus enhances long-term potentiation and long-term contextual but not cued fear memory in rats. J Neurosci 2016; 36: 4313–4324.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

    He YY, Xue YX, Wang JS, Fang Q, Liu JF, Xue LF et al. PKMzeta maintains drug reward and aversion memory in the basolateral amygdala and extinction memory in the infralimbic cortex. Neuropsychopharmacology 2011; 36: 1972–1981.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Tsokas P, Hsieh C, Yao Y, Lesburgueres E, Wallace EJ, Tcherepanov A et al. Compensation for PKMzeta in long-term potentiation and spatial long-term memory in mutant mice. Elife 2016; 5: e14846.

    PubMed  PubMed Central  Google Scholar 

  52. 52

    Wu-Zhang AX, Schramm CL, Nabavi S, Malinow R, Newton AC. Cellular pharmacology of protein kinase Mzeta (PKMzeta) contrasts with its in vitro profile: implications for PKMzeta as a mediator of memory. J Biol Chem 2012; 287: 12879–12885.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Ren SQ, Yan JZ, Zhang XY, Bu YF, Pan WW, Yao W et al. PKClambda is critical in AMPA receptor phosphorylation and synaptic incorporation during LTP. EMBO J 2013; 32: 1365–1380.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Sebastian V, Estil JB, Chen D, Schrott LM, Serrano PA. Acute physiological stress promotes clustering of synaptic markers and alters spine morphology in the hippocampus. PLoS ONE 2013; 8: e79077.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55

    Cohen H, Kozlovsky N, Matar MA, Kaplan Z, Zohar J. Mapping the brain pathways of traumatic memory: inactivation of protein kinase M zeta in different brain regions disrupts traumatic memory processes and attenuates traumatic stress responses in rats. Eur Neuropsychopharmacol 2010; 20: 253–271.

    CAS  PubMed  Google Scholar 

  56. 56

    Sadeh N, Verbitsky S, Dudai Y, Segal M. Zeta inhibitory peptide, a candidate inhibitor of protein kinase Mzeta, is excitotoxic to cultured hippocampal neurons. J Neurosci 2015; 35: 12404–12411.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Brachman RA, McGowan JC, Perusini JN, Lim SC, Pham TH, Faye C et al. Ketamine as a prophylactic against stress-induced depressive-like behavior. Biol Psychiatry 2016; 79: 776–786.

    CAS  PubMed  Google Scholar 

  58. 58

    Iniguez SD, Aubry A, Riggs LM, Alipio JB, Zanca RM, Flores-Ramirez FJ et al. Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice. Neurobiol Stress 2016; 5: 54–64.

    PubMed  PubMed Central  Google Scholar 

  59. 59

    Wang YX, Zhang XR, Zhang ZJ, Li L, Xi GJ, Wu D et al. Protein kinase Mzeta is involved in the modulatory effect of fluoxetine on hippocampal neurogenesis in vitro. Int J Neuropsychopharmacol 2014; 17: 1429–1441.

    CAS  PubMed  Google Scholar 

  60. 60

    Castillo-Padilla DV, Funke K. Effects of chronic iTBS-rTMS and enriched environment on visual cortex early critical period and visual pattern discrimination in dark-reared rats. Dev Neurobiol 2016; 76: 19–33.

    CAS  PubMed  Google Scholar 

  61. 61

    Evuarherhe O, Barker GR, Savalli G, Warburton EC, Brown MW. Early memory formation disrupted by atypical PKC inhibitor ZIP in the medial prefrontal cortex but not hippocampus. Hippocampus 2014; 24: 934–942.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Hernandez AI, Oxberry WC, Crary JF, Mirra SS, Sacktor TC. Cellular and subcellular localization of PKMzeta. Philos Trans R Soc Lond B Biol Sci 2014; 369: 20130140.

    PubMed  PubMed Central  Google Scholar 

  63. 63

    Yao Y, Kelly MT, Sajikumar S, Serrano P, Tian D, Bergold PJ et al. PKM zeta maintains late long-term potentiation by N-ethylmaleimide-sensitive factor/GluR2-dependent trafficking of postsynaptic AMPA receptors. J Neurosci 2008; 28: 7820–7827.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    Sacktor TC. How does PKMzeta maintain long-term memory? Nat Rev Neurosci 2011; 12: 9–15.

    CAS  PubMed  Google Scholar 

  65. 65

    Migues PV, Hardt O, Wu DC, Gamache K, Sacktor TC, Wang YT et al. PKMzeta maintains memories by regulating GluR2-dependent AMPA receptor trafficking. Nat Neurosci 2010; 13: 630–634.

    CAS  PubMed  Google Scholar 

  66. 66

    Feyissa AM, Chandran A, Stockmeier CA, Karolewicz B. Reduced levels of NR2A and NR2B subunits of NMDA receptor and PSD-95 in the prefrontal cortex in major depression. Prog Neuropsychopharmacol Biol Psychiatry 2009; 33: 70–75.

    CAS  PubMed  Google Scholar 

  67. 67

    Yuen EY, Wei J, Liu W, Zhong P, Li X, Yan Z. Repeated stress causes cognitive impairment by suppressing glutamate receptor expression and function in prefrontal cortex. Neuron 2012; 73: 962–977.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Serrano P, Yao Y, Sacktor TC. Persistent phosphorylation by protein kinase Mzeta maintains late-phase long-term potentiation. J Neurosci 2005; 25: 1979–1984.

    CAS  PubMed  Google Scholar 

  69. 69

    Tominaga-Yoshino K, Urakubo T, Okada M, Matsuda H, Ogura A. Repetitive induction of late-phase LTP produces long-lasting synaptic enhancement accompanied by synaptogenesis in cultured hippocampal slices. Hippocampus 2008; 18: 281–293.

    CAS  PubMed  Google Scholar 

  70. 70

    Zunszain PA, Horowitz MA, Cattaneo A, Lupi MM, Pariante CM. Ketamine: synaptogenesis, immunomodulation and glycogen synthase kinase-3 as underlying mechanisms of its antidepressant properties. Mol Psychiatry 2013; 18: 1236–1241.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71

    Liu RJ, Aghajanian GK. Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc Natl Acad Sci USA 2008; 105: 359–364.

    CAS  PubMed  Google Scholar 

  72. 72

    Radley JJ, Sisti HM, Hao J, Rocher AB, McCall T, Hof PR et al. Chronic behavioral stress induces apical dendritic reorganization in pyramidal neurons of the medial prefrontal cortex. Neuroscience 2004; 125: 1–6.

    CAS  PubMed  Google Scholar 

  73. 73

    Hajszan T, Dow A, Warner-Schmidt JL, Szigeti-Buck K, Sallam NL, Parducz A et al. Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol Psychiatry 2009; 65: 392–400.

    PubMed  Google Scholar 

  74. 74

    Tackenberg C, Ghori A, Brandt R. Thin, stubby or mushroom: spine pathology in Alzheimer's disease. Curr Alzheimer Res 2009; 6: 261–268.

    CAS  PubMed  Google Scholar 

  75. 75

    Ron S, Dudai Y, Segal M. Overexpression of PKMzeta alters morphology and function of dendritic spines in cultured cortical neurons. Cereb Cortex 2012; 22: 2519–2528.

    PubMed  Google Scholar 

  76. 76

    Yasumatsu N, Matsuzaki M, Miyazaki T, Noguchi J, Kasai H. Principles of long-term dynamics of dendritic spines. J Neurosci 2008; 28: 13592–13608.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Williams NR, Schatzberg AF. NMDA antagonist treatment of depression. Curr Opin Neurobiol 2016; 36: 112–117.

    CAS  PubMed  Google Scholar 

  78. 78

    Zarate CA Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry 2006; 63: 856–864.

    CAS  PubMed  Google Scholar 

  79. 79

    Diazgranados N, Ibrahim L, Brutsche NE, Newberg A, Kronstein P, Khalife S et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010; 67: 793–802.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

    Murrough JW, Iosifescu DV, Chang LC, Al Jurdi RK, Green CE, Perez AM et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013; 170: 1134–1142.

    PubMed  PubMed Central  Google Scholar 

  81. 81

    Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci 1997; 17: 2921–2927.

    CAS  PubMed  Google Scholar 

  82. 82

    Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA. Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 2003; 117: 697–706.

    CAS  PubMed  Google Scholar 

  83. 83

    Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med 2016; 22: 238–249.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Krystal JH, Sanacora G, Duman RS. Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond. Biol Psychiatry 2013; 73: 1133–1141.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 2016; 533: 481–486.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 2011; 475: 91–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS. BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol 2015; 18.

    PubMed  PubMed Central  Google Scholar 

  88. 88

    Maeng S, Zarate CA Jr., Du J, Schloesser RJ, McCammon J, Chen G et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 2008; 63: 349–352.

    CAS  PubMed  Google Scholar 

  89. 89

    Koike H, Iijima M, Chaki S. Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 2011; 224: 107–111.

    CAS  PubMed  Google Scholar 

  90. 90

    Kelly MT, Crary JF, Sacktor TC. Regulation of protein kinase Mzeta synthesis by multiple kinases in long-term potentiation. J Neurosci 2007; 27: 3439–3444.

    CAS  PubMed  Google Scholar 

  91. 91

    Ignacio ZM, Reus GZ, Arent CO, Abelaira HM, Pitcher MR, Quevedo J. New perspectives on the involvement of mTOR in depression as well as in the action of antidepressant drugs. Br J Clin Pharmacol 2016; 82: 1280–1290.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

This work was supported in part by the National Basic Research Program of China (no. 2015CB856400 and 2015CB553503), National Natural Science Foundation of China (no. 81521063, 31230033, and 91432303) and Peking University (no. BMU20160555).

Author information

Affiliations

Authors

Corresponding author

Correspondence to L Lu.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Yan, W., Liu, JF., Han, Y. et al. Protein kinase Mζ in medial prefrontal cortex mediates depressive-like behavior and antidepressant response. Mol Psychiatry 23, 1878–1891 (2018). https://doi.org/10.1038/mp.2017.219

Download citation

Further reading

Search

Quick links