Changes in apical dendritic structure correlate with sustained ERK1/2 phosphorylation in medial prefrontal cortex of a rat model of dopamine D1 receptor agonist sensitization.
Rats lesioned with 6-hydroxydopamine (6-OHDA) as neonates exhibit behavioral and neurochemical abnormalities in adulthood that mimic Lesch-Nyhan disease, schizophrenia, and other developmental disorders of frontostriatal circuit dysfunction. In these animals a latent sensitivity to D1 agonists is maximally exposed by repeated administration of dopamine agonists in the postpubertal period (D1 priming). In neonate-lesioned, adult rats primed with SKF-38393, we found selective, persistent alterations in the morphology of pyramidal neuron apical dendrites in the prelimbic area of the medial prefrontal cortex (mPFC). In these animals, dendrite bundling patterns and the typically straight trajectories of primary dendritic shafts were disrupted, whereas the diameter of higher-order oblique branches was increased. Although not present in neonate-lesioned rats treated with saline, these morphological changes persisted at least 21 days after repeated dosing with SKF-38393, and were not accompanied by markers of neurodegenerative change. A sustained increase in phospho-ERK immunoreactivity in wavy dendritic shafts over the same period suggested a relationship between prolonged ERK phosphorylation and dendritic remodeling in D1-primed rats. In support of this hypothesis, pretreatment with the MEK1/2-ERK1/2 pathway inhibitors PD98059 or SL327, prior to each priming dose of SKF-38393, prevented the morphological changes associated with D1 priming. Together, these findings demonstrate that repeated stimulation of D1 receptors in adulthood interacts with the developmental loss of dopamine to profoundly and persistently modify neuronal signaling and dendrite morphology in the mature prefrontal cortex. Furthermore, sustained elevation of ERK activity in mPFC pyramidal neurons may play a role in guiding these morphological changes in vivo.
Papadeas
Sophia T
ST
Graduate Program in Neurobiology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Halloran
Christopher
C
McCown
Thomas J
TJ
Breese
George R
GR
Blake
Bonita L
BL
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000378:metabolism*; D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D003712:Dendrites / Q000648:ultrastructure*; D018491:Dopamine Agonists / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000033:anatomy & histology* / Q000187:drug effects / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism; D013565:Sympatholytics / Q000633:toxicity
D018491:Dopamine Agonists; D005419:Flavonoids; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; D011480:Protease Inhibitors; D017447:Receptors, Dopamine D1; C424127:SL 327; D013565:Sympatholytics; D000607:Aminoacetonitrile; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
J Neurosci. 2000 Jun 15;20(12):4606-14
10844030
Anal Biochem. 1989 Sep;181(2):259-66
2573292
Curr Opin Neurobiol. 2003 Jun;13(3):391-8
12850225
Brain Res Brain Res Rev. 2005 Feb;48(1):57-73
15708628
Brain Res. 2005 Nov 16;1062(1-2):166-70
16257395
Brain Res. 1994 May 9;645(1-2):49-60
8062100
Curr Opin Neurobiol. 2004 Jun;14(3):311-7
15194111
Cereb Cortex. 1996 May-Jun;6(3):431-45
8670669
Biotechniques. 2000 Feb;28(2):216-8
10683726
J Pharmacol Exp Ther. 1992 Aug;262(2):855-65
1354257
J Neurochem. 1994 Dec;63(6):2336-41
7525876
J Neurosci. 1989 Jan;9(1):125-33
2521511
J Neurochem. 2003 Jul;86(2):351-62
12871576
Dev Cell. 2003 Apr;4(4):521-33
12689591
Exp Neurol. 2002 Jul;176(1):66-74
12093083
Neurochem Res. 2007 Apr-May;32(4-5):707-15
17024568
J Comp Neurol. 1985 Nov 15;241(3):253-67
2418068
Nature. 1996 Jul 25;382(6589):363-6
8684467
Endocr Rev. 2001 Apr;22(2):153-83
11294822
J Neurosci Res. 1999 Oct 1;58(1):42-61
10491571
J Comp Neurol. 2005 Jul 4;487(3):270-82
15892099
Curr Opin Neurobiol. 2000 Jun;10(3):381-91
10851172
Int J Dev Neurosci. 2004 Nov;22(7):507-14
15465280
J Comp Neurol. 2003 Dec 1;467(1):119-33
14574684
J Biol Chem. 1998 Jul 17;273(29):18623-32
9660836
Ann N Y Acad Sci. 1986;466:145-66
3089105
J Neurosci. 2004 Jun 30;24(26):5863-76
15229233
Neuron. 2002 Jun 13;34(6):985-98
12086645
J Biol Chem. 1995 Nov 17;270(46):27489-94
7499206
J Biol Chem. 2000 Apr 21;275(16):12200-6
10766856
J Neurosci. 2000 Dec 1;20(23):8701-9
11102476
Neuron. 1996 Feb;16(2):357-68
8789950
Mol Ther. 2006 Jul;14(1):63-8
16730475
Brain Res. 1990 Apr 2;512(2):284-90
2162235
J Pharmacol Exp Ther. 1985 Aug;234(2):447-55
3926987
J Neurosci. 1999 Jun 15;19(12):4907-20
10366625
Int J Neuropsychopharmacol. 2004 Mar;7 Suppl 1:S7-S13
14972079
J Neurosci. 1999 May 1;19(9):3535-44
10212313
Prog Neurobiol. 2000 Jun;61(2):133-68
10704996
J Pharmacol Exp Ther. 1984 Nov;231(2):343-54
6149306
Neuron. 2002 Jun 13;34(6):999-1010
12086646
J Neurosci. 2002 Oct 1;22(19):8597-606
12351733
Nat Rev Neurosci. 2004 Jan;5(1):45-54
14708003
Mol Biol Cell. 1996 Jun;7(6):893-905
8816996
Nat Neurosci. 1998 Nov;1(7):602-9
10196568
Cell Mol Life Sci. 2005 Sep;62(17):1913-24
15990959
J Neurosci. 2003 Dec 10;23(36):11420-6
14673006
Neuropharmacology. 2004;47 Suppl 1:33-46
15464124
Neurobiol Dis. 2005 Nov;20(2):479-90
15908225
Biochem J. 2000 Oct 1;351(Pt 1):95-105
10998351
J Neurobiol. 2005 Feb 5;62(2):278-88
15514998
Brain Res. 2001 May 18;901(1-2):79-84
11368953
J Neurosci. 1996 Dec 1;16(23):7627-37
8922419
Nat Neurosci. 2001 Feb;4(2):151-8
11175875
J Comp Neurol. 2006 Jun 1;496(4):529-43
16572431
Neuroscientist. 2006 Feb;12(1):16-28
16394190
Eur J Biochem. 2004 Jun;271(11):2060-6
15153095
N Engl J Med. 1996 Jun 13;334(24):1568-72
8628337
Trends Neurosci. 1997 Jun;20(6):269-74
9185309
Neuroscience. 2001;106(1):5-14
11564412
J Neurosci. 1997 Dec 15;17(24):9596-604
9391014
Exp Brain Res. 2004 Oct;158(3):265-77
15365664
Brain Res Brain Res Rev. 2000 Apr;32(2-3):449-75
10760551
Brain Res. 1998 Nov 9;810(1-2):181-99
9813316
Neuroscience. 1993 Jul;55(2):463-72
8377938
Exp Brain Res. 1997 May;114(3):433-41
9187279
J Neurobiol. 2005 Jul;64(1):4-10
15884010
Neuroscience. 2001;105(4):1041-54
11530241
J Neurophysiol. 2001 Feb;85(2):926-37
11160523
Proc Natl Acad Sci U S A. 1995 Sep 12;92(19):8881-5
7568036
Brain Res. 1996 Aug 19;730(1-2):75-86
8883891
Neuroscience. 2005;133(2):463-70
15878241
Trends Neurosci. 2000 Feb;23(2):59
10652545
J Neurosci. 2007 Oct 24;27(43):11473-82
17959790
Brain Res. 1989 Jan 23;478(1):127-37
2538199