title: Synaptic Plasticity, Metaplasticity and Depression.
abstract: The development of a persistent depressive affective state has for some time been thought to result from persistent alterations in neurotransmitter-mediated synaptic transmission. While the identity of those transmitters has changed over the years, the literature has lacked mechanistic connections between the neurophysiological mechanisms they regulate, and how these mechanisms alter neuronal function, and, hence, affective homeostasis. This review will examine recent work that suggests that both long-term activity-dependent changes in synaptic strength ("plasticity"), and shifting set points for the ease of induction of future long-term changes ("metaplasticity"), may be critical to establishing and reversing a depressive behavioral state. Activitydependent long-term synaptic plasticity involves both strengthening and weakening of synaptic connections associated with a dizzying array of neurochemical alterations that include synaptic insertion and removal of a number of subtypes of AMPA, NMDA and metabotropic glutamate receptors, changes in presynaptic glutamate release, and structural changes in dendritic spines. Cellular mechanisms of metaplasticity are far less well understood. Here, we will review the growing evidence that long-term synaptic changes in glutamatergic transmission, in brain regions that regulate mood, are key determinants of affective homeostasis and therapeutic targets with immense potential for drug development.
authors.forename: Linnea R
authors.initials: LR
authors.lastname: Vose
authors.affiliation: Department of Cell Biology & Anatomy, New York Medical College, Valhalla, NY, 10595, USA.
authors.forename: Patric K
authors.initials: PK
authors.lastname: Stanton
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology* / Q000503:physiopathology; D003863:Depression / Q000473:pathology*; D006801:Humans; D009473:Neuronal Plasticity / Q000502:physiology*; D017470:Receptors, Glutamate / Q000378:metabolism*; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D017470:Receptors, Glutamate
references.citation: Hippocampus. 2009 Sep;19(9):828-36
references.pmid: 19235231
references.citation: Physiol Behav. 2003 Aug;79(3):417-27
references.pmid: 12954436
references.citation: J Psychopharmacol. 2013 May;27(5):444-50
references.pmid: 23428794
references.citation: Mol Neurobiol. 2012 Oct;46(2):304-15
references.pmid: 22717988
references.citation: J Clin Psychopharmacol. 1982 Apr;2(2):129-33
references.pmid: 7042771
references.citation: Br J Pharmacol. 1994 Jan;111(1):364-9
references.pmid: 8012720
references.citation: Epilepsia. 2007;48 Suppl 9:23-5
references.pmid: 18047596
references.citation: J Sleep Res. 2015 Aug;24(4):407-13
references.pmid: 25824847
references.citation: Science. 1990 Jun 29;248(4963):1619-24
references.pmid: 2114039
references.citation: Cereb Cortex. 2004 Feb;14(2):224-9
references.pmid: 14704220
references.citation: J Neurophysiol. 1988 Aug;60(2):645-63
references.pmid: 2902200
references.citation: Biol Psychiatry. 2000 Oct 15;48(8):755-65
references.pmid: 11063972
references.citation: Hippocampus. 2012 Feb;22(2):188-99
references.pmid: 21069779
references.citation: Brain Res. 1990 Oct 29;531(1-2):225-31
references.pmid: 1705153
references.citation: Eur J Pharmacol. 1994 Jan 15;266(2):187-92
references.pmid: 8157072
references.citation: Biol Psychiatry. 2007 Dec 1;62(11):1310-6
references.pmid: 17574216
references.citation: Biol Psychiatry. 2015 Dec 15;78(12):830-9
references.pmid: 25823790
references.citation: Proc Natl Acad Sci U S A. 2001 Jun 19;98(13):7101-6
references.pmid: 11416194
references.citation: Brain Stimul. 2013 May;6(3):424-32
references.pmid: 22695026
references.citation: Psychiatry Res. 2015 May 30;232(2):162-7
references.pmid: 25862529
references.citation: Eur J Pharmacol. 1988 Dec 13;158(3):199-205
references.pmid: 3253098
references.citation: J Clin Psychiatry. 2013 Oct;74(10):966-73
references.pmid: 24229746
references.citation: Neuropsychopharmacology. 2013 Apr;38(5):729-42
references.pmid: 23303054
references.citation: Trends Neurosci. 1997 Nov;20(11):523-9
references.pmid: 9364667
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):13069-74
references.pmid: 14557544
references.citation: JAMA. 2007 Dec 5;298(21):2540-2
references.pmid: 18056908
references.citation: Brain Res Dev Brain Res. 1989 Sep 1;49(1):105-14
references.pmid: 2551539
references.citation: Neuroscience. 2011 May 19;182:88-97
references.pmid: 21440043
references.citation: Psychopharmacology (Berl). 2014 May;231(10):2107-16
references.pmid: 24264567
references.citation: Nature. 1984 May 17-23;309(5965):261-3
references.pmid: 6325946
references.citation: Proc Natl Acad Sci U S A. 1997 May 13;94(10):5401-4
references.pmid: 9144249
references.citation: Eur J Neurosci. 2005 Nov;22(10):2451-61
references.pmid: 16307588
references.citation: Science. 2000 Mar 24;287(5461):2262-7
references.pmid: 10731148
references.citation: Hum Psychopharmacol. 2001 Jan;16(1):9-21
references.pmid: 12404593
references.citation: Neuropharmacology. 2005 Dec;49(7):1077-87
references.pmid: 16051282
references.citation: CNS Neurol Disord Drug Targets. 2014;13(4):567-73
references.pmid: 24168367
references.citation: Exp Clin Psychopharmacol. 1997 May;5(2):107-12
references.pmid: 9234045
references.citation: Curr Neurovasc Res. 2010 Nov;7(4):268-80
references.pmid: 20854252
references.citation: Science. 1996 Nov 8;274(5289):972-6
references.pmid: 8875937
references.citation: Nat Rev Neurosci. 2009 Jun;10(6):434-45
references.pmid: 19401723
references.citation: J Neuropsychiatry Clin Neurosci. 1998 Winter;10(1):20-5
references.pmid: 9547462
references.citation: Neurosci Biobehav Rev. 2011 Oct;35(9):1982-8
references.pmid: 21718719
references.citation: J Cereb Blood Flow Metab. 2002 Jan;22(1):89-96
references.pmid: 11807398
references.citation: Schizophr Res. 2004 Aug 1;69(2-3):317-23
references.pmid: 15469203
references.citation: Neurobiol Aging. 2015 Jun;36(6):2136-44
references.pmid: 25834937
references.citation: Ann Med. 2013 Jun;45(4):308-21
references.pmid: 23687987
references.citation: Neuron. 2005 Mar 3;45(5):651-60
references.pmid: 15748841
references.citation: Biol Psychiatry. 2013 Aug 15;74(4):250-6
references.pmid: 22840761
references.citation: Science. 2002 Mar 1;295(5560):1729-34
references.pmid: 11872844
references.citation: Expert Opin Investig Drugs. 2014 Feb;23(2):243-54
references.pmid: 24251380
references.citation: Neuropharmacology. 2012 Feb;62(2):617-27
references.pmid: 21736888
references.citation: Neurochem Res. 2015 May;40(5):942-51
references.pmid: 25749890
references.citation: Behav Brain Res. 2005 Aug 30;163(1):78-90
references.pmid: 15913801
references.citation: J Neurosci. 2006 Apr 12;26(15):3951-8
references.pmid: 16611811
references.citation: Neuropsychopharmacology. 1999 Feb;20(2):106-18
references.pmid: 9885791
references.citation: Biol Psychiatry. 2006 Oct 1;60(7):722-9
references.pmid: 16934776
references.citation: Neuroscience. 1995 Nov;69(1):89-98
references.pmid: 8637636
references.citation: Proc Natl Acad Sci U S A. 2014 Jun 10;111(23):8649-54
references.pmid: 24912158
references.citation: Science. 1989 Apr 14;244(4901):224-6
references.pmid: 2704997
references.citation: Behav Brain Res. 2015 Nov 1;294:177-85
references.pmid: 26210936
references.citation: Neuroscience. 1997 Mar;77(1):65-73
references.pmid: 9044375
references.citation: Eur J Neurosci. 2007 May;25(10):3109-14
references.pmid: 17561824
references.citation: J Neurosci. 1999 Jul 15;19(14):RC18
references.pmid: 10407060
references.citation: Emotion. 2007 May;7(2):227-38
references.pmid: 17516802
references.citation: Neuropharmacology. 2013 Nov;74:32-40
references.pmid: 23628345
references.citation: Exp Brain Res. 1992;89(2):275-87
references.pmid: 1623973
references.citation: J Neurobiol. 2006 Feb 15;66(3):205-19
references.pmid: 16329119
references.citation: Biol Psychiatry. 2010 Jan 15;67(2):101-9
references.pmid: 19819427
references.citation: Neurochem Res. 2003 Nov;28(11):1735-42
references.pmid: 14584827
references.citation: Biol Psychiatry. 2002 Sep 1;52(5):404-12
references.pmid: 12242056
references.citation: Biol Psychiatry. 2010 Jan 15;67(2):168-74
references.pmid: 19811775
references.citation: Brain Res. 2003 Sep 5;983(1-2):128-36
references.pmid: 12914973
references.citation: Neuroscience. 2006 Jun 30;140(2):597-606
references.pmid: 16600515
references.citation: J Comp Physiol Psychol. 1973 Feb;82(2):175-81
references.pmid: 4571892
references.citation: Behav Brain Res. 2014 Dec 15;275:191-200
references.pmid: 25192638
references.citation: J Neurosci. 1988 Nov;8(11):4079-88
references.pmid: 3183713
references.citation: J Neurosci. 1996 May 15;16(10):3534-40
references.pmid: 8627386
references.citation: Proc Natl Acad Sci U S A. 2015 May 12;112(19):6188-93
references.pmid: 25918363
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13176-81
references.pmid: 17656555
references.citation: Mol Psychiatry. 2015 Apr;20(4):482-9
references.pmid: 24912492
references.citation: J Pharmacol Sci. 2014;124(4):457-67
references.pmid: 24646653
references.citation: Philos Trans R Soc Lond B Biol Sci. 2013 Dec 02;369(1633):20130151
references.pmid: 24298153
references.citation: Neuroscience. 2015 Nov 12;308:202-11
references.pmid: 26343295
references.citation: PLoS One. 2013 Apr 09;8(4):e61046
references.pmid: 23593384
references.citation: J Neurophysiol. 1996 Aug;76(2):953-62
references.pmid: 8871210
references.citation: Depress Anxiety. 2015 Aug;32(8):594-604
references.pmid: 25917683
references.citation: Nature. 1996 May 2;381(6577):71-5
references.pmid: 8609991
references.citation: Eur J Neurosci. 2003 May;17(9):1928-34
references.pmid: 12752792
references.citation: Psychosom Med. 2014 Jan;76(1):80-5
references.pmid: 24367123
references.citation: Stress. 2012 Jan;15(1):11-20
references.pmid: 21682654
references.citation: Nat Med. 2014 May;20(5):531-5
references.pmid: 24728411
references.citation: Science. 1992 Feb 7;255(5045):730-3
references.pmid: 1346729
references.citation: Neuron. 2005 Jan 20;45(2):201-6
references.pmid: 15664172
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7746-50
references.pmid: 12032354
references.citation: J Res Med Sci. 2014 Jun;19(6):525-30
references.pmid: 25197294
references.citation: Biol Psychiatry. 2007 Jan 15;61(2):240-5
references.pmid: 16876135
references.citation: Curr Mol Pharmacol. 2009 Jan;2(1):77-82
references.pmid: 20021448
references.citation: Cereb Cortex. 2006 Mar;16(3):313-20
references.pmid: 15901656
references.citation: Neuroscience. 2005;131(1):43-54
references.pmid: 15680690
references.citation: Neuroscience. 2004;128(4):667-73
references.pmid: 15464275
references.citation: Neuropharmacology. 2008 Dec;55(7):1238-50
references.pmid: 18796308
references.citation: J Neurosci. 2002 Jul 1;22(13):5525-35
references.pmid: 12097504
references.citation: Neuropharmacology. 2008 Sep;55(4):454-8
references.pmid: 18606173
references.citation: Physiol Behav. 1999 Jan 1-15;65(4-5):723-37
references.pmid: 10073474
references.citation: J Math Biol. 1977 Oct 20;4(4):303-21
references.pmid: 925522
references.citation: Br J Pharmacol. 2015 May;172(9):2354-68
references.pmid: 25560396
references.citation: Lancet. 1996 Jul 27;348(9022):233-7
references.pmid: 8684201
references.citation: Clin EEG Neurosci. 2007 Apr;38(2):105-15
references.pmid: 17515176
references.citation: Neuropharmacology. 2014 May;80:3-17
references.pmid: 24418102
references.citation: Neuropharmacology. 1997 Nov-Dec;36(11-12):1517-32
references.pmid: 9517422
references.citation: Psychiatry Res. 2015 Jan 30;225(1-2):1-13
references.pmid: 25467702
references.citation: J Neurosci. 2014 Dec 10;34(50):16762-73
references.pmid: 25505329
references.citation: Neuroreport. 1993 May;4(5):591-4
references.pmid: 8390312
references.citation: Neuroscience. 1995 Nov;69(1):83-8
references.pmid: 8637635
references.citation: J Neurosci. 2007 Mar 14;27(11):2781-7
references.pmid: 17360899
references.citation: J Neurosci. 2002 Sep 1;22(17):7453-61
references.pmid: 12196567
references.citation: Neuroscience. 2009 Dec 1;164(2):798-808
references.pmid: 19723561
references.citation: Am J Psychiatry. 2004 Oct;161(10):1848-55
references.pmid: 15465982
references.citation: Neuroscience. 2010 Sep 15;169(4):1705-14
references.pmid: 20600655
references.citation: J Neurosci. 2002 Aug 1;22(15):6810-8
references.pmid: 12151561
references.citation: Cell Mol Neurobiol. 2001 Aug;21(4):357-68
references.pmid: 11775066
references.citation: Neuropharmacology. 1995 Jan;34(1):1-26
references.pmid: 7623957
references.citation: Steroids. 2014 Dec;91:20-31
references.pmid: 25173821
references.citation: Neuroscientist. 2011 Feb;17(1):124-44
references.pmid: 20236945
references.citation: Behav Brain Res. 2015 Jun 1;286:175-83
references.pmid: 25746514
references.citation: Hosp Community Psychiatry. 1991 Mar;42(3):293-6
references.pmid: 2030013
references.citation: Cell Mol Life Sci. 2015 Sep;72(18):3521-9
references.pmid: 26037722
references.citation: Aust N Z J Psychiatry. 2008 Dec;42(12):995-1002
references.pmid: 19016087
references.citation: Neurochem Res. 2008 Dec;33(12):2436-43
references.pmid: 18438710
references.citation: BMC Neurosci. 2007 Dec 19;8:107
references.pmid: 18093285
references.citation: Hippocampus. 1998;8(2):160-70
references.pmid: 9572722
references.citation: Hippocampus. 2008;18(6):548-63
references.pmid: 18306298
references.citation: Psychoneuroendocrinology. 2014 Aug;46:129-40
references.pmid: 24882165
references.citation: Annu Rev Neurosci. 2000;23:155-84
references.pmid: 10845062
references.citation: Neuropharmacology. 1993 Jan;32(1):1-9
references.pmid: 8381524
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:218-24
references.pmid: 25582770
references.citation: Neuroreport. 2014 Dec 3;25(17):1331-7
references.pmid: 25304495
references.citation: Cereb Cortex. 2010 Oct;20(10):2433-41
references.pmid: 20080931
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11378-83
references.pmid: 22733766
references.citation: Brain Res. 1995 Oct 2;694(1-2):312-7
references.pmid: 8974660
references.citation: Steroids. 2014 Dec;91:11-9
references.pmid: 24928721
references.citation: Behav Brain Res. 2015 Apr 1;282:176-84
references.pmid: 25591480
references.citation: J Psychoactive Drugs. 2001 Apr-Jun;33(2):151-8
references.pmid: 11476262
references.citation: Eur J Neurosci. 2006 Nov;24(10):2917-22
references.pmid: 17156214
references.citation: Biol Psychiatry. 2013 Nov 15;74(10):742-9
references.pmid: 23751205
references.citation: Nature. 1989 May 18;339(6221):215-8
references.pmid: 2716848
references.citation: Neuropharmacology. 2012 Feb;62(2):674-85
references.pmid: 21596050
references.citation: J Psychiatr Pract. 2015 Mar;21(2):140-9
references.pmid: 25782764
references.citation: Pharmacol Rep. 2013;65(6):1572-9
references.pmid: 24553005
references.citation: Nature. 1989 Mar 30;338(6214):425-7
references.pmid: 2538755
references.citation: Learn Mem. 1996 Sep-Oct;3(2-3):138-49
references.pmid: 10456084
references.citation: J Neurosci. 1993 Jul;13(7):2910-8
references.pmid: 8331379
references.citation: Neural Plast. 2012;2012:728161
references.pmid: 22548195
references.citation: Physiol Behav. 1998 Aug;65(1):43-9
references.pmid: 9811363
references.citation: Biol Psychiatry. 2009 Mar 1;65(5):392-400
references.pmid: 19006787
references.citation: J Neurosci. 2009 Mar 18;29(11):3395-403
references.pmid: 19295146
references.citation: J Neurosci. 2003 Jun 1;23(11):4406-9
references.pmid: 12805280
references.citation: Science. 1995 Sep 22;269(5231):1730-4
references.pmid: 7569903
references.citation: Neuropsychopharmacology. 2008 Jun;33(7):1603-10
references.pmid: 17712352
references.citation: Nat Med. 2012 Sep;18(9):1413-7
references.pmid: 22885997
references.citation: Neurosci Lett. 1997 Sep 12;233(1):41-4
references.pmid: 9324235
references.citation: Gen Physiol Biophys. 2015 Oct;34(4):353-66
references.pmid: 25926550
references.citation: Physiol Behav. 2015 May 15;144:1-6
references.pmid: 25758931
references.citation: Science. 1999 Jun 11;284(5421):1811-6
references.pmid: 10364548
references.citation: PLoS One. 2010 Jan 05;5(1):e8566
references.pmid: 20052403
references.citation: Pharmacol Rep. 2013;65(5):1163-75
references.pmid: 24399712
references.citation: Learn Mem. 2008 Apr 07;15(4):261-70
references.pmid: 18391187
references.citation: Neuroscience. 2006 Dec 1;143(2):387-93
references.pmid: 16962717
references.citation: Psychoneuroendocrinology. 2014 Apr;42:77-88
references.pmid: 24636504
references.citation: Brain Res. 2008 Aug 21;1226:27-32
references.pmid: 18582439
references.citation: Eur J Pharmacol. 2001 Oct 19;429(1-3):23-37
references.pmid: 11698024
references.citation: Stress. 2015;18(4):419-26
references.pmid: 25938810
references.citation: J Neurosci. 2013 Jul 24;33(30):12218-28
references.pmid: 23884930
references.citation: Neurochem Int. 2009 Jul-Aug;55(1-3):85-97
references.pmid: 19428811
references.citation: Pharmacol Biochem Behav. 2012 Feb;100(4):752-74
references.pmid: 21569789
references.citation: PLoS One. 2015 Apr 21;10(4):e0123565
references.pmid: 25898204
references.citation: Science. 1995 Mar 17;267(5204):1662-6
references.pmid: 7886458
references.citation: Compr Psychiatry. 2015 May;59:54-61
references.pmid: 25749480
references.citation: Am J Psychiatry. 2003 Aug;160(8):1516-8
references.pmid: 12900317
references.citation: J Neurosci. 1982 Jan;2(1):32-48
references.pmid: 7054394
references.citation: Neuropharmacology. 2008 Sep;55(3):353-62
references.pmid: 18359495
references.citation: J Neurosci. 2007 Jul 4;27(27):7130-5
references.pmid: 17611266
references.citation: Psychoneuroendocrinology. 2015 May;55:128-43
references.pmid: 25765754
references.citation: Mol Psychiatry. 2013 Dec;18(12):1265-72
references.pmid: 23128153
references.citation: Psychopharmacology (Berl). 2015 Jan;232(1):185-95
references.pmid: 24958230
references.citation: Nat Med. 2013 Mar;19(3):337-44
references.pmid: 23416703
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15537-42
references.pmid: 17881561
references.citation: Physiol Rep. 2013 Oct;1(5):e00133
references.pmid: 24303196
references.citation: Neurobiol Dis. 2015 Oct;82:254-61
references.pmid: 26102021
references.citation: Neuroscience. 2012 Jun 14;212:1-18
references.pmid: 22542678
references.citation: Neuropsychopharmacology. 2015 Nov;40(12 ):2666-75
references.pmid: 25953359
references.citation: Nat Neurosci. 1999 Jan;2(1):37-43
references.pmid: 10195178
references.citation: Asian J Psychiatr. 2015 Jun;15:5-9
references.pmid: 25998093
references.citation: Behav Brain Res. 1994 May 30;62(1):1-9
references.pmid: 7917027
references.citation: Arch Gen Psychiatry. 2006 Oct;63(10):1121-9
references.pmid: 17015814