title: Glutamate receptors as targets of protein kinase C in the pathophysiology and treatment of animal models of mania.
abstract: Considerable biochemical evidence suggests that the protein kinase C (PKC) signaling cascade may be a convergent point for the actions of anti-manic agents, and that excessive PKC activation can disrupt prefrontal cortical regulation of thinking and behavior. To date, however, brain protein targets of PKC's anti-manic effects have not been fully identified. Here we showed that PKC activity was enhanced in the prefrontal cortex of animals treated with the psychostimulant amphetamine. Phosphorylation of MARCKS, a marker of PKC activity, was increased in the prefrontal cortex of animals treated with the psychostimulant amphetamine, as well as in sleep-deprived animals (another animal model of mania), but decreased in lithium-treated animals. The antidepressant imipramine, which shows pro-manic properties in patients with bipolar disorder (BPD), also enhanced phospho-MARCKS in prefrontal cortex in vivo. We further explored the functional targets of PKC in mania-associated behaviors. Neurogranin is a brain-specific, postsynaptically located PKC substrate. PKC phosphorylation of neurogranin was robustly increased by pro-manic manipulations and decreased by anti-manic agents. PKC phosphorylation of the NMDA receptor site GluN1S896 and the AMPA receptor site GluA1T840 was also enhanced in the prefrontal cortex of animals treated with the antidepressant imipramine, as well as in behaviorally sleep-deprived animals, in striking contrast to the reduced activity seen in lithium-treated animals. These results suggest that PKC may play an important role in regulating NMDA and AMPA receptor functions. The biochemical profile of the PKC pathway thus encompasses both pro- and anti-manic effects on behavior. These results suggest that PKC modulators or their intracellular targets may ultimately represent novel avenues for the development of new therapeutics for mood disorders.
authors.affiliation: Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Building 35, 1C912, Bethesda, MD 20892, USA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Szabo
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Machado-Vieira
authors.forename: Peixiong
authors.initials: P
authors.lastname: Yuan
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wei
authors.forename: Cynthia
authors.initials: C
authors.lastname: Falke
authors.forename: Chiara
authors.initials: C
authors.lastname: Cirelli
authors.forename: Giulio
authors.initials: G
authors.lastname: Tononi
authors.forename: Husseini K
authors.initials: HK
authors.lastname: Manji
authors.forename: Jing
authors.initials: J
authors.lastname: Du
mesh_terms: D000661:Amphetamine / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology / Q000627:therapeutic use*; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D018021:Lithium Chloride / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D051579:Neurogranin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D011921:Rats, Inbred WKY; D017470:Receptors, Glutamate / Q000378:metabolism*; D012892:Sleep Deprivation
chemical_list: D000929:Antidepressive Agents, Tricyclic; D000697:Central Nervous System Stimulants; D047908:Intracellular Signaling Peptides and Proteins; C000619711:Marcks protein, mouse; C000619712:Marcks protein, rat; D008565:Membrane Proteins; D017470:Receptors, Glutamate; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D051579:Neurogranin; D000661:Amphetamine; D011493:Protein Kinase C; D018021:Lithium Chloride; D007099:Imipramine
references.citation: Sheng Li Ke Xue Jin Zhan. 2003 Apr;34(2):111-5
references.pmid: 12889141
references.citation: Biol Psychiatry. 2000 Sep 15;48(6):518-30
references.pmid: 11018224
references.citation: Hum Mol Genet. 2002 Jun 1;11(12):1373-80
references.pmid: 12023979
references.citation: Brain Res. 1992 Jan 20;570(1-2):333-40
references.pmid: 1617424
references.citation: J Biochem. 1998 Apr;123(4):760-5
references.pmid: 9538272
references.citation: Nat Rev Drug Discov. 2008 May;7(5):426-37
references.pmid: 18425072
references.citation: Biol Psychiatry. 1997 Mar 15;41(6):649-56
references.pmid: 9066988
references.citation: Ann N Y Acad Sci. 2003 Nov;1003:273-91
references.pmid: 14684452
references.citation: J Psychiatry Neurosci. 2007 May;32(3):160-1
references.pmid: 17476362
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1997 Apr;21(3):455-86
references.pmid: 9153068
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1997 Apr;21(3):507-29
references.pmid: 9153070
references.citation: J Neurochem. 1994 Dec;63(6):2361-4
references.pmid: 7964759
references.citation: Biol Psychiatry. 2008 Feb 15;63(4):349-52
references.pmid: 17643398
references.citation: Biol Psychiatry. 2003 Apr 15;53(8):707-42
references.pmid: 12706957
references.citation: Nat Neurosci. 2008 Feb;11(2):200-8
references.pmid: 18204445
references.citation: Biol Psychiatry. 2006 Apr 15;59(8):713-20
references.pmid: 16460696
references.citation: J Neurosci. 2000 Jan 1;20(1):89-102
references.pmid: 10627585
references.citation: Synapse. 2003 Dec 1;50(3):212-22
references.pmid: 14515339
references.citation: Neuropsychologia. 2003;41(11):1474-83
references.pmid: 12849765
references.citation: Biol Psychiatry. 2006 Jun 15;59(12):1151-9
references.pmid: 16566899
references.citation: Annu Rev Pharmacol Toxicol. 1993;33:45-70
references.pmid: 8098596
references.citation: Neurosurgery. 1993 Sep;33(3):495-501; discussion 501
references.pmid: 8413883
references.citation: Neuropsychobiology. 2007;55(3-4):123-31
references.pmid: 17641532
references.citation: Bipolar Disord. 2000 Sep;2(3 Pt 2):217-36
references.pmid: 11249800
references.citation: Arch Gen Psychiatry. 2004 Jul;61(7):685-93
references.pmid: 15237080
references.citation: Neuropharmacology. 2001 Nov;41(6):672-9
references.pmid: 11640921
references.citation: Mol Psychiatry. 1998 Nov;3(6):534-8
references.pmid: 9857980
references.citation: Mol Psychiatry. 2008 Feb;13(2):197-207
references.pmid: 17486107
references.citation: J Clin Psychiatry. 1998 Jul;59(7):374-9
references.pmid: 9714266
references.citation: J Neurosci. 2004 Jul 21;24(29):6578-89
references.pmid: 15269270
references.citation: Harefuah. 2004 Jun;143(6):420-5, 462
references.pmid: 15524099
references.citation: Mol Cell Neurosci. 2007 Sep;36(1):86-94
references.pmid: 17689977
references.citation: CNS Spectr. 2005 Oct;10(10):808-19
references.pmid: 16400244
references.citation: Neuropharmacology. 1992 Dec;31(12):1211-22
references.pmid: 1361666
references.citation: Neuron Glia Biol. 2004 Aug;1(3):231-43
references.pmid: 18634600
references.citation: J Neurochem. 1999 Dec;73(6):2299-309
references.pmid: 10582587
references.citation: Curr Psychiatry Rep. 2007 Dec;9(6):467-74
references.pmid: 18221626
references.citation: Trends Neurosci. 2002 Dec;25(12):610-5
references.pmid: 12446127
references.citation: Biol Psychiatry. 2006 Jun 1;59(11):1006-20
references.pmid: 16487491
references.citation: Am J Psychiatry. 1999 Dec;156(12):1986-8
references.pmid: 10588416
references.citation: Bipolar Disord. 1999 Dec;1(2):81-6
references.pmid: 11252663
references.citation: Biol Psychiatry. 1996 Oct 1;40(7):568-75
references.pmid: 8886289
references.citation: Science. 2005 Nov 25;310(5752):1340-3
references.pmid: 16311338
references.citation: Neuropsychologia. 1987;25(2):359-65
references.pmid: 3601041
references.citation: Neuron. 2006 Jul 20;51(2):213-25
references.pmid: 16846856
references.citation: Science. 2004 Oct 29;306(5697):882-4
references.pmid: 15514161
references.citation: J Neurochem. 1993 Nov;61(5):1722-30
references.pmid: 8228988
references.citation: J Biol Chem. 1997 Dec 26;272(52):32727-30
references.pmid: 9407043
references.citation: Curr Psychiatry Rep. 2000 Dec;2(6):479-89
references.pmid: 11122999
references.citation: J Neurochem. 1996 Jun;66(6):2402-9
references.pmid: 8632163
references.citation: Neuropharmacology. 2007 Jul;53(1):27-36
references.pmid: 17543354
references.citation: Arch Gen Psychiatry. 2008 Mar;65(3):255-63
references.pmid: 18316672
references.citation: Neuron. 2007 Mar 1;53(5):703-17
references.pmid: 17329210
references.citation: Arch Gen Psychiatry. 2003 Jun;60(6):601-9
references.pmid: 12796223
references.citation: Neuropharmacology. 1992 Dec;31(12):1201-10
references.pmid: 1361665
references.citation: Neuropsychopharmacology. 2007 Apr;32(4):793-802
references.pmid: 16936714
references.citation: Neuropsychopharmacology. 2002 Jan;26(1):14-7
references.pmid: 11751028
references.citation: Neuron. 2003 Apr 24;38(2):157-60
references.pmid: 12718851
references.citation: Pharmacol Ther. 2001 Feb;89(2):149-70
references.pmid: 11316518
references.citation: Biol Psychiatry. 2006 Apr 1;59(7):611-8
references.pmid: 16414030
references.citation: J Pharmacol Exp Ther. 1998 Apr;285(1):307-16
references.pmid: 9536026
references.citation: Biol Psychiatry. 1999 Nov 15;46(10):1328-51
references.pmid: 10578449
references.citation: J Affect Disord. 2003 Jan;73(1-2):123-31
references.pmid: 12507745
references.citation: Eur Neuropsychopharmacol. 1995;5 Suppl:89-93
references.pmid: 8775765
references.citation: Neurochem Int. 2005 Jul;47(1-2):84-91
references.pmid: 15936117
references.citation: J Clin Psychiatry. 1996;57 Suppl 13:23-31; discussion 32-3
references.pmid: 8970502
references.citation: J Neurosci. 2000 Jun 15;20(12):4480-8
references.pmid: 10844017
references.citation: Ann N Y Acad Sci. 2003 Nov;1003:378-80
references.pmid: 14684466
references.citation: Arch Gen Psychiatry. 2000 Jan;57(1):95-7
references.pmid: 10632242
references.citation: J Psychiatr Res. 2003 Sep-Oct;37(5):421-32
references.pmid: 12849934
references.citation: J Biol Chem. 2000 Jun 9;275(23):17894-9
references.pmid: 10749878
references.citation: Int J Neuropsychopharmacol. 2007 Oct;10(5):621-9
references.pmid: 16978443
references.citation: Neuropsychopharmacology. 2007 Dec;32(12):2511-9
references.pmid: 17356571
references.citation: J Neurochem. 2004 Jun;89(5):1119-25
references.pmid: 15147504
references.citation: Curr Drug Targets. 2001 Sep;2(3):299-312
references.pmid: 11554554
references.citation: Biol Psychiatry. 1998 Nov 1;44(9):909-11
references.pmid: 9807646
references.citation: J Neurochem. 1993 Dec;61(6):2303-10
references.pmid: 8245981
references.citation: Bipolar Disord. 2007 Sep;9(6):561-70
references.pmid: 17845270
references.citation: Synapse. 1997 Jul;26(3):281-91
references.pmid: 9183817
references.citation: Biochemistry. 2000 Jun 20;39(24):7291-9
references.pmid: 10852729
references.citation: J Clin Psychiatry. 2000;61 Suppl 9:5-15
references.pmid: 10826655
references.citation: J Neurosci. 2008 Jan 2;28(1):68-79
references.pmid: 18171924
references.citation: Pharmacol Ther. 2006 Dec;112(3):810-32
references.pmid: 16904750
references.citation: J Neurosci. 1999 May 15;19(10):3674-80
references.pmid: 10233999
references.citation: Exp Neurol. 2008 May;211(1):7-10
references.pmid: 18291371
references.citation: J Neurochem. 2002 Nov;83(3):704-12
references.pmid: 12390532
references.citation: Neuron. 1996 Jun;16(6):1179-88
references.pmid: 8663994
references.citation: J Biol Chem. 2002 May 31;277(22):19498-505
references.pmid: 11912190
references.citation: J Clin Psychiatry. 1999 Nov;60(11):733-40
references.pmid: 10584760
references.citation: Biofactors. 1990 Jul;2(3):171-8
references.pmid: 2116134
references.citation: Neurology. 1986 Feb;36(2):212-6
references.pmid: 3945393