title: D1 and D2 dopamine receptors in separate circuits cooperate to drive associative long-term potentiation in the prefrontal cortex.
abstract: Dopamine release associated with motivational arousal is thought to drive goal-directed learning and consolidation of acquired memories. This dopamine hypothesis of learning and motivation directly suggests that dopamine is necessary for modifications of excitatory synapses in dopamine terminal fields, including the prefrontal cortex (PFC), to "stamp in" posttrial memory traces. It is unknown how such enabling occurs in native circuits tightly controlled by GABAergic inhibitory tone. Here we report that dopamine, via both D1-class receptors (D1Rs) and D2-class receptors (D2Rs), enables the induction of spike timing-dependent long-term potentiation (t-LTP) in layer V PFC pyramidal neurons over a "window" of more than 30 ms that is otherwise closed under intact inhibitory constraint. Dopamine acts at D2Rs in local GABAergic interneurons to suppress inhibitory transmission, gating the induction of t-LTP. Moreover, dopamine activates postsynaptic D1Rs in excitatory synapses to allow t-LTP induction at a substantially extended, normally ineffective, timing interval (+30 ms), thus increasing the associability of prepost coincident stimuli. Although the D2R-mediated disinhibition alone is sufficient to gate t-LTP at a normal timing (+10 ms), t-LTP at +30 ms requires concurrent activation of both D1Rs and D2Rs. Our results illustrate a previously unrecognized circuit-level mechanism by which dopamine receptors in separate microcircuits cooperate to drive Hebbian synaptic plasticity across a significant temporal window under intact inhibition. This mechanism should be important in functioning of interconnected PFC microcircuits, in which D1Rs and D2Rs are not colocalized but their coactivation is necessary.
authors.affiliation: Division of Neurosciences, New England Primate Research Center, Harvard Medical School, Southborough, MA 01772, USA.
authors.forename: Tai-Xiang
authors.initials: TX
authors.lastname: Xu
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Yao
mesh_terms: D000818:Animals; D015640:Ion Channel Gating; D017774:Long-Term Potentiation; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D009435:Synaptic Transmission; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D005680:gamma-Aminobutyric Acid
references.citation: J Neurosci. 2003 Jun 15;23(12):5079-87
references.pmid: 12832531
references.citation: J Neurosci. 2009 Nov 11;29(45):14086-99
references.pmid: 19906957
references.citation: Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13028-33
references.pmid: 19620735
references.citation: J Neurosci. 1998 Dec 15;18(24):10464-72
references.pmid: 9852584
references.citation: Neuron. 1999 Jul;23(3):435-47
references.pmid: 10433257
references.citation: J Neurosci. 2010 May 26;30(21):7236-48
references.pmid: 20505090
references.citation: J Neurophysiol. 1996 Nov;76(5):2896-906
references.pmid: 8930242
references.citation: Nat Neurosci. 2003 Jun;6(6):587-92
references.pmid: 12740581
references.citation: Psychopharmacology (Berl). 2006 Nov;188(4):567-85
references.pmid: 16670842
references.citation: J Comp Neurol. 2005 Aug 8;488(4):464-75
references.pmid: 15973684
references.citation: J Neurophysiol. 2001 Dec;86(6):2911-8
references.pmid: 11731547
references.citation: Annu Rev Neurosci. 2001;24:139-66
references.pmid: 11283308
references.citation: J Neurosci. 2001 May 15;21(10):3628-38
references.pmid: 11331392
references.citation: Neuron. 2004 Sep 30;44(1):5-21
references.pmid: 15450156
references.citation: Nature. 1983 Feb 17-23;301(5901):603-4
references.pmid: 6298626
references.citation: Cereb Cortex. 2003 Nov;13(11):1251-6
references.pmid: 14576216
references.citation: J Neurosci. 2003 May 15;23(10):4173-81
references.pmid: 12764105
references.citation: J Neurosci. 2006 May 3;26(18):4803-10
references.pmid: 16672653
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14146-50
references.pmid: 17709755
references.citation: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2836-41
references.pmid: 12591942
references.citation: Nat Rev Neurosci. 2004 Jun;5(6):483-94
references.pmid: 15152198
references.citation: Neuron. 2007 Sep 20;55(6):919-29
references.pmid: 17880895
references.citation: J Neurosci. 2003 Mar 1;23(5):1622-30
references.pmid: 12629166
references.citation: J Comp Neurol. 1996 May 20;369(1):1-15
references.pmid: 8723699
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3236-41
references.pmid: 14981263
references.citation: Annu Rev Neurosci. 1992;15:285-320
references.pmid: 1575444
references.citation: Neuron. 2006 May 18;50(4):521-4
references.pmid: 16701201
references.citation: J Neurophysiol. 1971 Jul;34(4):532-51
references.pmid: 4329778
references.citation: Curr Opin Neurobiol. 1999 Jun;9(3):288-92
references.pmid: 10395568
references.citation: Science. 1997 Jan 10;275(5297):209-13
references.pmid: 8985013
references.citation: J Neurosci. 2008 Mar 5;28(10):2435-46
references.pmid: 18322089
references.citation: J Neurosci. 2003 Dec 3;23(35):11142-6
references.pmid: 14657173
references.citation: Prog Neurobiol. 2004 Sep;74(1):1-58
references.pmid: 15381316
references.citation: Neuron. 2001 Aug 2;31(2):191-201
references.pmid: 11502252
references.citation: Annu Rev Physiol. 2002;64:355-405
references.pmid: 11826273
references.citation: Neuron. 2001 Dec 20;32(6):1149-64
references.pmid: 11754844
references.citation: J Neurophysiol. 2002 Dec;88(6):3150-66
references.pmid: 12466437
references.citation: Science. 1996 Nov 15;274(5290):1133-8
references.pmid: 8895456
references.citation: J Neurophysiol. 1999 Mar;81(3):967-76
references.pmid: 10085325
references.citation: Synapse. 2006 Jun 1;59(7):412-7
references.pmid: 16485264
references.citation: Science. 1997 Jan 10;275(5297):213-5
references.pmid: 8985014
references.citation: J Neurosci. 2000 Nov 15;20(22):RC106
references.pmid: 11069975
references.citation: Nature. 2005 Oct 13;437(7061):1027-31
references.pmid: 16222299
references.citation: Neuron. 2007 Apr 5;54(1):73-87
references.pmid: 17408579
references.citation: Science. 2001 Aug 10;293(5532):1159-63
references.pmid: 11498596
references.citation: J Neurosci. 1993 Jun;13(6):2551-64
references.pmid: 8501521
references.citation: Trends Neurosci. 2004 Jan;27(1):30-40
references.pmid: 14698608
references.citation: J Neurosci. 1998 Dec 15;18(24):10553-65
references.pmid: 9852592
references.citation: Science. 2008 Aug 8;321(5890):848-51
references.pmid: 18687967
references.citation: Neuron. 1996 Apr;16(4):815-23
references.pmid: 8607999
references.citation: Nat Rev Neurosci. 2005 Apr;6(4):312-24
references.pmid: 15803162
references.citation: Proc Natl Acad Sci U S A. 1989 Nov;86(22):9015-9
references.pmid: 2573073
references.citation: Neuron. 2002 Oct 10;36(2):241-63
references.pmid: 12383780
references.citation: Nature. 1996 May 16;381(6579):245-8
references.pmid: 8622768
references.citation: Annu Rev Neurosci. 2008;31:25-46
references.pmid: 18275283