title: Long-term behavioral programming induced by peripuberty stress in rats is accompanied by GABAergic-related alterations in the Amygdala.
abstract: Stress during childhood and adolescence is a risk factor for psychopathology. Alterations in γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, have been found following stress exposure and fear experiences and are often implicated in anxiety and mood disorders. Abnormal amygdala functioning has also been detected following stress exposure and is also implicated in anxiety and social disorders. However, the amygdala is not a unitary structure; it includes several nuclei with different functions and little is known on the potential differences the impact of early life stress may have on this system within different amygdaloid nuclei. We aimed here to evaluate potential regional differences in the expression of GABAergic-related markers across several amygdaloid nuclei in adult rats subjected to a peripuberty stress protocol that leads to enhanced basal amygdala activity and psychopathological behaviors. More specifically, we investigated the protein expression levels of glutamic acid decarboxylase (GAD; the principal synthesizing enzyme of GABA) and of GABA-A receptor subunits α2 and α3. We found reduced GAD and GABA-A α3, but not α2, subunit protein levels throughout all the amygdala nuclei examined (lateral, basolateral, basomedial, medial and central) and increased anxiety-like behaviors and reduced sociability in peripubertally stressed animals. Our results identify an enduring inhibition of the GABAergic system across the amygdala following exposure to early adversity. They also highlight the suitability of the peripuberty stress model to investigate the link between treatments targeting the dysfunctional GABAergic system in specific amygdala nuclei and recovery of specific stress-induced behavioral dysfunctions.
authors.affiliation: Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Stamatina
authors.initials: S
authors.lastname: Tzanoulinou
authors.affiliation: Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Valencia, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: García-Mompó
authors.affiliation: Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Valencia, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Castillo-Gómez
authors.affiliation: Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Vandana
authors.initials: V
authors.lastname: Veenit
authors.affiliation: Neurobiology Unit and Program in Basic and Applied Neurosciences, Cell Biology Department, Universitat de València, Valencia, Spain; CIBERSAM: Spanish National Network for Research in Mental Health, Madrid, Spain; Fundacion Investigacion Hospital Clinico de Valencia, INCLIVA, Valencia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Nacher
authors.affiliation: Laboratory of Behavioral Genetics, Brain Mind Institute, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Carmen
authors.initials: C
authors.lastname: Sandi
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000523:psychology; D001522:Behavior, Animal; D001835:Body Weight; D005106:Exploratory Behavior; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007398:Interpersonal Relations; D011627:Puberty / Q000378:metabolism / Q000523:psychology*; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D013315:Stress, Psychological / Q000378:metabolism* / Q000523:psychology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C520011:Gabra2 protein, rat; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D005968:Glutamate Decarboxylase
references.citation: Stress. 2012 Jul;15(4):416-24
references.pmid: 22044189
references.citation: Eur Neuropsychopharmacol. 2007 Jul;17(8):546-57
references.pmid: 17307340
references.citation: J Neurophysiol. 2009 Mar;101(3):1629-46
references.pmid: 19036872
references.citation: Neurobiol Learn Mem. 2012 Jul;98(1):93-101
references.pmid: 22664720
references.citation: Brain Res Bull. 2006 Feb 15;68(6):419-24
references.pmid: 16459196
references.citation: J Neurosci. 2009 Jan 7;29(1):1-2
references.pmid: 19129378
references.citation: Behav Brain Res. 2008 Mar 5;187(2):228-38
references.pmid: 17945360
references.citation: Eur J Pharmacol. 2008 May 13;585(2-3):473-82
references.pmid: 18417120
references.citation: Physiol Behav. 1994 Apr;55(4):747-53
references.pmid: 8190805
references.citation: Brain Res Rev. 2008 Mar;57(2):571-85
references.pmid: 18164765
references.citation: Physiol Rev. 1992 Jul;72(3):825-52
references.pmid: 1320764
references.citation: Neuropharmacology. 2012 Aug;63(2):250-8
references.pmid: 22465203
references.citation: Hippocampus. 2004;14(3):292-300
references.pmid: 15132428
references.citation: J Clin Psychiatry. 2004;65 Suppl 1:11-7
references.pmid: 14728092
references.citation: Psychopharmacol Bull. 2003;37(4):133-46
references.pmid: 15131523
references.citation: Mol Psychiatry. 2009 Mar;14(3):234-5
references.pmid: 19229201
references.citation: Schizophr Res. 2005 Jan 1;72(2-3):109-22
references.pmid: 15560956
references.citation: Psychoneuroendocrinology. 2009 Jul;34(6):844-58
references.pmid: 19181453
references.citation: Brain Res. 1991 Dec 13;567(1):101-10
references.pmid: 1667743
references.citation: J Neurosci. 2004 Apr 7;24(14):3471-9
references.pmid: 15071094
references.citation: J Neurosci. 1984 Jan;4(1):251-64
references.pmid: 6693941
references.citation: Neuron. 2005 Oct 20;48(2):175-87
references.pmid: 16242399
references.citation: Neurochem Res. 1995 May;20(5):631-6
references.pmid: 7643969
references.citation: Neural Plast. 2007;2007:71203
references.pmid: 17671613
references.citation: Dev Psychobiol. 2012 Jul;54(5):546-55
references.pmid: 22072233
references.citation: Life Sci. 1998;63(15):1289-303
references.pmid: 9768867
references.citation: Pharmacol Biochem Behav. 1986 Mar;24(3):525-9
references.pmid: 2871560
references.citation: Depress Anxiety. 1997;5(2):66-72
references.pmid: 9262936
references.citation: Br J Pharmacol. 2005 Feb;144(3):357-66
references.pmid: 15655523
references.citation: Ann N Y Acad Sci. 2003 Apr;985:389-410
references.pmid: 12724173
references.citation: J Comp Neurol. 1986 Mar 22;245(4):553-65
references.pmid: 3009561
references.citation: Trends Neurosci. 2009 Jun;32(6):312-20
references.pmid: 19409624
references.citation: Biol Psychiatry. 2006 Aug 15;60(4):322-8
references.pmid: 16919522
references.citation: Int J Neuropsychopharmacol. 2011 Jul;14(6):721-34
references.pmid: 21226980
references.citation: Psychopharmacology (Berl). 2011 Feb;213(4):697-706
references.pmid: 20922362
references.citation: F1000 Biol Rep. 2011 Jan 14;3:2
references.pmid: 21399763
references.citation: Biol Psychiatry. 2002 Oct 15;52(8):805-10
references.pmid: 12372652
references.citation: Trends Neurosci. 1997 Nov;20(11):517-23
references.pmid: 9364666
references.citation: Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1698-703
references.pmid: 9990087
references.citation: Synapse. 2002 Aug;45(2):86-94
references.pmid: 12112401
references.citation: Psychopharmacology (Berl). 2011 Mar;214(1):55-70
references.pmid: 20865251
references.citation: J Neurosci. 2012 Jun 20;32(25):8611-9
references.pmid: 22723702
references.citation: Mol Psychiatry. 2006 Aug;11(8):752-62
references.pmid: 16718280
references.citation: Transl Psychiatry. 2013 Jan 15;3:e216
references.pmid: 23321813
references.citation: Psychopharmacology (Berl). 2011 May;215(2):311-9
references.pmid: 21190016
references.citation: Exp Neurol. 2011 Nov;232(1):33-40
references.pmid: 21819983
references.citation: Psychopharmacol Bull. 2007;40(1):8-30
references.pmid: 17285093
references.citation: Proc Natl Acad Sci U S A. 2012 Oct 2;109(40):16330-5
references.pmid: 22992651
references.citation: Biol Psychiatry. 2006 Aug 15;60(4):376-82
references.pmid: 16919525
references.citation: Child Adolesc Psychiatr Clin N Am. 2003 Apr;12(2):293-317, ix
references.pmid: 12725013
references.citation: Depress Anxiety. 2012 Mar;29(3):202-9
references.pmid: 21994092
references.citation: Neuron. 1991 Jul;7(1):91-100
references.pmid: 2069816
references.citation: Biol Psychiatry. 1990 May 15;27(10):1094-102
references.pmid: 2340320
references.citation: Curr Opin Pharmacol. 2006 Feb;6(1):18-23
references.pmid: 16376150
references.citation: J Comp Neurol. 1995 Aug 14;359(1):154-94
references.pmid: 8557845
references.citation: PLoS One. 2013;8(1):e55248
references.pmid: 23383124
references.citation: Transl Psychiatry. 2012 Apr 24;2:e106
references.pmid: 22832906
references.citation: Pharmacol Biochem Behav. 1995 Dec;52(4):701-6
references.pmid: 8587908
references.citation: Am J Psychiatry. 2000 Jul;157(7):1120-6
references.pmid: 10873921
references.citation: Pharmacol Ther. 2012 Nov;136(2):142-52
references.pmid: 22921455
references.citation: J Histochem Cytochem. 1981 Apr;29(4):577-80
references.pmid: 6166661
references.citation: Nat Rev Neurosci. 2008 Dec;9(12):947-57
references.pmid: 19002191
references.citation: Mol Psychiatry. 2008 Jan;13(1):74-83, 3
references.pmid: 17667960
references.citation: Eur J Pharmacol. 2005 Dec 5;526(1-3):89-100
references.pmid: 16280125
references.citation: Trends Neurosci. 2008 Apr;31(4):183-91
references.pmid: 18329735
references.citation: J Neurosci. 2007 Apr 18;27(16):4482-91
references.pmid: 17442833
references.citation: Trends Pharmacol Sci. 2012 Nov;33(11):611-20
references.pmid: 22981367
references.citation: Neurosci Biobehav Rev. 2012 Jan;36(1):459-78
references.pmid: 21855571
references.citation: Biol Psychiatry. 2004 Mar 15;55(6):603-11
references.pmid: 15013829
references.citation: Brain Res. 2000 Dec 22;887(1):23-33
references.pmid: 11134586
references.citation: Hippocampus. 2011 Jan;21(1):56-71
references.pmid: 19921700
references.citation: Neuropharmacology. 2012 Jan;62(1):42-53
references.pmid: 21889518
references.citation: PLoS One. 2009;4(1):e4329
references.pmid: 19180243
references.citation: Biol Psychiatry. 2005 Jul 15;58(2):111-8
references.pmid: 16038681
references.citation: J Neurosci. 2005 Nov 16;25(46):10682-8
references.pmid: 16291941
references.citation: Front Behav Neurosci. 2011 Apr 07;5:17
references.pmid: 21519389
references.citation: Arch Gen Psychiatry. 2005 Mar;62(3):282-8
references.pmid: 15753241
references.citation: Behav Brain Res. 1994 Nov 16;65(1):47-55
references.pmid: 7880454
references.citation: PLoS One. 2013;8(2):e56871
references.pmid: 23451101
references.citation: Trends Pharmacol Sci. 2001 Apr;22(4):188-94
references.pmid: 11282419
references.citation: Biol Psychiatry. 2006 Mar 1;59(5):424-9
references.pmid: 16256956
references.citation: Behav Brain Res. 2010 Dec 25;214(2):268-76
references.pmid: 20561965
references.citation: Genes Brain Behav. 2004 Oct;3(5):287-302
references.pmid: 15344922
references.citation: Trends Pharmacol Sci. 1998 Dec;19(12):500-5
references.pmid: 9871412
references.citation: J Psychiatr Res. 2014 Jun;53:1-7
references.pmid: 24630468
references.citation: Int J Neuropsychopharmacol. 2008 Nov;11(7):891-903
references.pmid: 18364065
references.citation: Psychopharmacology (Berl). 1995 Sep;121(1):118-26
references.pmid: 8539336
references.citation: Biol Psychiatry. 2001 Jun 15;49(12):1023-39
references.pmid: 11430844
references.citation: Ann N Y Acad Sci. 1988;525:281-90
references.pmid: 2455462
references.citation: J Clin Psychiatry. 2003;64 Suppl 3:21-7
references.pmid: 12662130
references.citation: Neuropsychopharmacology. 1999 Jul;21(1):40-50
references.pmid: 10379518
references.citation: Am J Psychiatry. 2007 Oct;164(10):1476-88
references.pmid: 17898336
references.citation: Behav Brain Res. 2011 Oct 1;223(2):403-10
references.pmid: 21536077
references.citation: Neuropsychopharmacology. 2010 Jan;35(1):169-91
references.pmid: 19625997
references.citation: Neuropsychopharmacology. 2000 Mar;22(3):219-29
references.pmid: 10693149
references.citation: Eur J Neurosci. 2004 Sep;20(5):1281-9
references.pmid: 15341600
references.citation: Brain Res. 2009 Apr 24;1267:65-76
references.pmid: 19268657
references.citation: Alcohol Clin Exp Res. 2007 Jun;31(6):1061-70
references.pmid: 17428292
references.citation: Arch Gen Psychiatry. 1998 Aug;55(8):715-20
references.pmid: 9707382
references.citation: Neuroscience. 2009 Dec 1;164(2):387-97
references.pmid: 19699782
references.citation: Arch Gen Psychiatry. 2008 Oct;65(10):1166-75
references.pmid: 18838633
references.citation: Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):8866-71
references.pmid: 22615410
references.citation: Brain Struct Funct. 2008 Sep;213(1-2):63-72
references.pmid: 18696110
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 1993 Nov;17(6):887-903
references.pmid: 8278600
references.citation: Front Behav Neurosci. 2013 Apr 04;7:26
references.pmid: 23576965
references.citation: J Neurosci. 2002 Aug 1;22(15):6810-8
references.pmid: 12151561
references.citation: Neuropharmacology. 2010 Mar-Apr;58(4-5):746-57
references.pmid: 20035774
references.citation: Trends Neurosci. 1997 Feb;20(2):78-84
references.pmid: 9023876
references.citation: Neuroscience. 2007 Jan 5;144(1):8-16
references.pmid: 17049177
references.citation: Clin Neurophysiol. 2006 Mar;117(3):637-42
references.pmid: 16426890
references.citation: Genes Brain Behav. 2003 Oct;2(5):255-67
references.pmid: 14606691
references.citation: Adv Biochem Psychopharmacol. 1995;48:41-56
references.pmid: 7653325
references.citation: Physiol Behav. 2007 Dec 5;92(5):824-30
references.pmid: 17651767