title: Sustained N-methyl-d-aspartate receptor hypofunction remodels the dopamine system and impairs phasic signaling.
abstract: Chronic N-methyl-d-aspartate receptor (NMDAR) hypofunction has been proposed as a contributing factor to symptoms of schizophrenia. However, it is unclear how sustained NMDAR hypofunction throughout development affects other neurotransmitter systems that have been implicated in the disease. Dopamine neuron biochemistry and activity were examined to determine whether sustained NMDAR hypofunction causes a state of hyperdopaminergia. We report that a global, genetic reduction in NMDARs led to a remodeling of dopamine neurons, substantially affecting two key regulators of dopamine homeostasis, i.e., tyrosine hydroxylase and the dopamine transporter. In NR1 knockdown mice, dopamine synthesis and release were attenuated, and dopamine clearance was increased. Although these changes would have the effect of reducing dopamine transmission, we demonstrated that a state of hyperdopaminergia existed in these mice because dopamine D2 autoreceptors were desensitized. In support of this conclusion, NR1 knockdown dopamine neurons have higher tonic firing rates. Although the tonic firing rates are higher, phasic signaling is impaired, and dopamine overflow cannot be achieved with exogenous high-frequency stimulation that models phasic firing. Through the examination of several parameters of dopamine neurotransmission, we provide evidence that chronic NMDAR hypofunction leads to a state of elevated synaptic dopamine. Compensatory mechanisms to attenuate hyperdopaminergia also impact the ability to generate dopamine surges through phasic firing.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ferris
authors.forename: Marija
authors.initials: M
authors.lastname: Milenkovic
authors.forename: Shuai
authors.initials: S
authors.lastname: Liu
authors.forename: Catharine A
authors.initials: CA
authors.lastname: Mielnik
authors.forename: Pieter
authors.initials: P
authors.lastname: Beerepoot
authors.forename: Carrie E
authors.initials: CE
authors.lastname: John
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: España
authors.forename: Tatyana D
authors.initials: TD
authors.lastname: Sotnikova
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Borgland
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Ramsey
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001921:Brain / Q000503:physiopathology*; D004298:Dopamine / Q000096:biosynthesis; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology*; D004558:Electric Stimulation; D055785:Gene Knockdown Techniques; D008564:Membrane Potentials / Q000502:physiology; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D018408:Patch-Clamp Techniques; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency* / Q000235:genetics; D009435:Synaptic Transmission / Q000502:physiology*; D046509:Tissue Culture Techniques; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; C121673:Gprin1 protein, mouse; D009419:Nerve Tissue Proteins; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine
keywords: 14-3-3; NMDA; burst firing; mouse; schizophrenia
references.citation: J Biol Chem. 2009 Nov 20;284(47):32758-69
references.pmid: 19801645
references.citation: Nat Neurosci. 2008 Dec;11(12):1376-7
references.pmid: 18978779
references.citation: Neuropsychopharmacology. 1995 Aug;13(1):9-19
references.pmid: 8526975
references.citation: Mol Pharmacol. 2009 Aug;76(2):396-404
references.pmid: 19460877
references.citation: Eur J Pharmacol. 1969 Jul;7(1):111-4
references.pmid: 5821798
references.citation: Neuropsychopharmacology. 1999 Mar;20(3):201-25
references.pmid: 10063482
references.citation: Nature. 1971 Nov 19;234(5325):152-3
references.pmid: 4942678
references.citation: Neuropsychopharmacology. 1999 Feb;20(2):106-18
references.pmid: 9885791
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 1;101(22):8467-72
references.pmid: 15159546
references.citation: Biol Psychiatry. 2011 Feb 1;69(3):201-7
references.pmid: 20801429
references.citation: Neurotox Res. 2006 Dec;10(3-4):221-33
references.pmid: 17197372
references.citation: Acta Physiol Scand. 1990 Jul;139(3):529-30
references.pmid: 2239353
references.citation: Behav Brain Res. 2004 Aug 31;153(2):507-19
references.pmid: 15265649
references.citation: J Neurosci. 1997 Aug 1;17(15):5738-46
references.pmid: 9221772
references.citation: FEBS Lett. 1987 Jul 13;219(1):79-82
references.pmid: 2885229
references.citation: Trends Neurosci. 2008 May;31(5):234-42
references.pmid: 18395805
references.citation: Arch Biochem Biophys. 2005 Feb 15;434(2):266-74
references.pmid: 15639226
references.citation: ACS Chem Neurosci. 2010 Mar 12;1(6):450-462
references.pmid: 20567609
references.citation: J Neurosci Methods. 2011 Nov 15;202(2):158-64
references.pmid: 21392532
references.citation: F1000 Biol Rep. 2010 Jan 18;2:
references.pmid: 20948813
references.citation: J Cell Biol. 1972 Dec;55(3):696-711
references.pmid: 4656707
references.citation: J Neurosci. 2003 Apr 1;23(7):2744-50
references.pmid: 12684460
references.citation: Neuron. 2002 Mar 14;33(6):921-33
references.pmid: 11906698
references.citation: Cell. 1999 Aug 20;98(4):427-36
references.pmid: 10481908
references.citation: Brain Res. 2000 Jul 7;870(1-2):73-9
references.pmid: 10869503
references.citation: Br J Pharmacol. 1996 Nov;119(5):869-76
references.pmid: 8922734
references.citation: J Neurosci. 2009 Feb 11;29(6):1735-42
references.pmid: 19211880
references.citation: Genes Brain Behav. 2009 Oct;8(7):661-75
references.pmid: 19563516
references.citation: Nature. 1976 Jun 24;261(5562):717-9
references.pmid: 945467
references.citation: Proc Natl Acad Sci U S A. 2009 May 5;106(18):7281-8
references.pmid: 19342487
references.citation: J Neurosci. 1996 Mar 15;16(6):2034-43
references.pmid: 8604048
references.citation: J Physiol. 2008 Apr 15;586(8):2157-70
references.pmid: 18308824
references.citation: Brain Res. 1981 Nov 30;225(2):373-85
references.pmid: 6118197
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):4029-34
references.pmid: 9520487
references.citation: Nat Neurosci. 2004 Jun;7(6):583-4
references.pmid: 15146188
references.citation: Am J Psychiatry. 1991 Oct;148(10):1301-8
references.pmid: 1654746
references.citation: Am J Psychiatry. 1976 Feb;133(2):197-202
references.pmid: 1251927
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4405-10
references.pmid: 18347339
references.citation: Psychopharmacology (Berl). 2006 Jan;184(2):190-200
references.pmid: 16362405
references.citation: Biol Psychiatry. 1999 Nov 15;46(10):1388-95
references.pmid: 10578453
references.citation: J Biol Chem. 2010 Jan 15;285(3):1957-66
references.pmid: 19903816
references.citation: Biol Psychiatry. 2013 May 1;73(9):860-8
references.pmid: 23305991
references.citation: J Neurosci. 2009 Jun 24;29(25):8215-24
references.pmid: 19553461
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 27;107(30):13491-6
references.pmid: 20616081
references.citation: Science. 1975 Nov 7;190(4214):522-8
references.pmid: 242074
references.citation: Science. 1992 Oct 23;258(5082):665-7
references.pmid: 1329209
references.citation: Anal Chem. 1996 Sep 15;68(18):3180-6
references.pmid: 8797378
references.citation: Front Syst Neurosci. 2011 May 11;5:28
references.pmid: 21617735
references.citation: Neuron. 2008 Aug 14;59(3):486-96
references.pmid: 18701073
references.citation: Neuron. 2008 Aug 14;59(3):497-508
references.pmid: 18701074
references.citation: Neuropsychopharmacology. 2001 Oct;25(4):455-67
references.pmid: 11557159
references.citation: Science. 2003 Mar 21;299(5614):1898-902
references.pmid: 12649484
references.citation: Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5795-800
references.pmid: 21436042
references.citation: J Neurophysiol. 2007 Oct;98(4):2297-310
references.pmid: 17699688
references.citation: J Neurosci. 2002 Jul 1;22(13):5462-72
references.pmid: 12097498
references.citation: Neuropsychopharmacology. 2008 Oct;33(11):2701-14
references.pmid: 18185498
references.citation: J Neurosci. 2003 Nov 19;23(33):10585-92
references.pmid: 14627643
references.citation: Nat Neurosci. 2007 Aug;10(8):1020-8
references.pmid: 17603481
references.citation: Brain Res Brain Res Rev. 2000 Mar;31(2-3):320-9
references.pmid: 10719159
references.citation: J Neurosci. 2011 Sep 28;31(39):13860-9
references.pmid: 21957248
references.citation: J Physiol. 1987 Nov;392:397-416
references.pmid: 2451725