title: Maternal immune activation leads to selective functional deficits in offspring parvalbumin interneurons.
abstract: Abnormalities in prefrontal gamma aminobutyric acid (GABA)ergic transmission, particularly in fast-spiking interneurons that express parvalbumin (PV), are hypothesized to contribute to the pathophysiology of multiple psychiatric disorders, including schizophrenia, bipolar disorder, anxiety disorders and depression. While primarily histological abnormalities have been observed in patients and in animal models of psychiatric disease, evidence for abnormalities in functional neurotransmission at the level of specific interneuron populations has been lacking in animal models and is difficult to establish in human patients. Using an animal model of a psychiatric disease risk factor, prenatal maternal immune activation (MIA), we found reduced functional GABAergic transmission in the medial prefrontal cortex (mPFC) of adult MIA offspring. Decreased transmission was selective for interneurons expressing PV, resulted from a decrease in release probability and was not observed in calretinin-expressing neurons. This deficit in PV function in MIA offspring was associated with increased anxiety-like behavior and impairments in attentional set shifting, but did not affect working memory. Furthermore, cell-type specific optogenetic inhibition of mPFC PV interneurons was sufficient to impair attentional set shifting and enhance anxiety levels. Finally, we found that in vivo mPFC gamma oscillations, which are supported by PV interneuron function, were linearly correlated with the degree of anxiety displayed in adult mice, and that this correlation was disrupted in MIA offspring. These results demonstrate a selective functional vulnerability of PV interneurons to MIA, leading to affective and cognitive symptoms that have high relevance for schizophrenia and other psychiatric disorders.
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Canetta
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bolkan
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.
authors.forename: N
authors.initials: N
authors.lastname: Padilla-Coreano
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, NY, USA.
authors.forename: L J
authors.initials: LJ
authors.lastname: Song
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Sahn
authors.affiliation: Department of Pharmacology, Columbia University Medical Center, New York, NY, USA.|Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.
authors.forename: N L
authors.initials: NL
authors.lastname: Harrison
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.|Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Gordon
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.|Department of Epidemiology, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA.|Divison of Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: A
authors.initials: A
authors.lastname: Brown
authors.affiliation: Department of Psychiatry, Columbia University Medical Center, New York, NY, USA.|Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA.|Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, NY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Kellendonk
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism; D006801:Humans; D007110:Immunity, Active; D007266:Inhibition, Psychological; D007395:Interneurons / Q000378:metabolism; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D010320:Parvalbumins / Q000276:immunology* / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D009435:Synaptic Transmission / Q000276:immunology / Q000502:physiology; D005680:gamma-Aminobutyric Acid
chemical_list: D010320:Parvalbumins; D005680:gamma-Aminobutyric Acid
references.citation: Neuron. 2006 Feb 16;49(4):603-15
references.pmid: 16476668
references.citation: Neuroscience. 2010 Nov 10;170(4):1110-9
references.pmid: 20736050
references.citation: Int Psychogeriatr. 2011 May;23(4):644-53
references.pmid: 21044398
references.citation: J Psychiatr Res. 2010 Jul;44(10):673-81
references.pmid: 20100621
references.citation: Am J Psychiatry. 2008 Apr;165(4):479-89
references.pmid: 18281411
references.citation: Curr Opin Neurobiol. 2010 Apr;20(2):199-204
references.pmid: 20167474
references.citation: J Psychiatr Res. 2009 Jul;43(11):970-7
references.pmid: 19321177
references.citation: J Affect Disord. 2015 Apr 1;175:241-7
references.pmid: 25658498
references.citation: Mol Psychiatry. 2008 Feb;13(2):147-61
references.pmid: 17471287
references.citation: Eur J Neurosci. 2012 Jun;35(12):1866-70
references.pmid: 22708597
references.citation: Brain Res. 2008 Jul 7;1218:267-77
references.pmid: 18534564
references.citation: Neural Plast. 2011;2011:723184
references.pmid: 21904685
references.citation: Nat Struct Mol Biol. 2007 Apr;14(4):280-6
references.pmid: 17384644
references.citation: Nat Rev Neurosci. 2007 Jan;8(1):45-56
references.pmid: 17180162
references.citation: Arch Gen Psychiatry. 2012 May;69(5):449-59
references.pmid: 22213769
references.citation: Curr Opin Neurobiol. 2014 Jun;26:22-6
references.pmid: 24650500
references.citation: Nature. 2014 Jan 2;505(7481):92-6
references.pmid: 24256726
references.citation: Behav Brain Res. 2011 Oct 10;224(1):180-8
references.pmid: 21679729
references.citation: Nature. 2009 Jun 4;459(7247):663-7
references.pmid: 19396156
references.citation: Biol Psychiatry. 2011 Apr 1;69(7):704-7
references.pmid: 21074144
references.citation: Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81
references.pmid: 22802640
references.citation: Arch Gen Psychiatry. 2008 Oct;65(10 ):1166-75
references.pmid: 18838633
references.citation: Am J Psychiatry. 2009 Jun;166(6):683-90
references.pmid: 19369317
references.citation: Nat Rev Neurosci. 2004 Oct;5(10):793-807
references.pmid: 15378039
references.citation: Am J Psychiatry. 2012 Oct;169(10):1082-91
references.pmid: 22983435
references.citation: Transl Psychiatry. 2014 Jul 29;4:e418
references.pmid: 25072323
references.citation: Schizophr Bull. 2015 Jan;41(1):180-91
references.pmid: 24361861
references.citation: Arch Gen Psychiatry. 2012 Feb;69(2):139-49
references.pmid: 21969419
references.citation: Brain Behav Immun. 2008 May;22(4):469-86
references.pmid: 18023140
references.citation: Arch Gen Psychiatry. 1995 Apr;52(4):258-66
references.pmid: 7702443
references.citation: J Clin Psychopharmacol. 1999 Jun;19(3):222-32
references.pmid: 10350028
references.citation: Behav Brain Res. 2014 Feb 1;259:24-34
references.pmid: 24177209
references.citation: Neuropsychopharmacology. 2014 Mar;39(4):1000-8
references.pmid: 24154667
references.citation: Neuropsychopharmacology. 2015 Sep;40(10):2475-86
references.pmid: 25904362
references.citation: J Neurophysiol. 2012 Aug;108(4):1211-22
references.pmid: 22539827
references.citation: J Comp Neurol. 2010 Feb 1;518(3):389-404
references.pmid: 19950390
references.citation: J Neurosci. 2003 Jan 1;23(1):297-302
references.pmid: 12514227
references.citation: Arch Gen Psychiatry. 1998 Aug;55(8):715-20
references.pmid: 9707382
references.citation: Mol Psychiatry. 2015 Dec;20(12):1499-507
references.pmid: 25623945
references.citation: Neuron. 2007 Feb 15;53(4):591-604
references.pmid: 17296559
references.citation: Schizophr Res. 2012 Sep;140(1-3):175-84
references.pmid: 22804924
references.citation: Isr J Psychiatry Relat Sci. 2006;43(1):10-5
references.pmid: 16910379
references.citation: Brain Res. 1997 Jan 2;744(1):179-84
references.pmid: 9030431
references.citation: Arch Gen Psychiatry. 2000 Nov;57(11):1061-9
references.pmid: 11074872
references.citation: Brain Res Bull. 2012 Feb 10;87(2-3):295-302
references.pmid: 21893170
references.citation: Behav Brain Res. 2009 Dec 7;204(2):313-21
references.pmid: 19136031
references.citation: Arch Gen Psychiatry. 2004 Jul;61(7):705-13
references.pmid: 15237082
references.citation: Biol Psychiatry. 2002 Mar 1;51(5):377-86
references.pmid: 11904132
references.citation: Am J Psychiatry. 2010 Mar;167(3):261-80
references.pmid: 20123911
references.citation: Arch Gen Psychiatry. 2007 Feb;64(2):193-200
references.pmid: 17283286
references.citation: Neuropsychopharmacology. 2015 Jan;40(1):190-206
references.pmid: 24759129
references.citation: J Neurosci. 1998 Jun 1;18(11):4244-54
references.pmid: 9592102
references.citation: Neuron. 2015 Mar 18;85(6):1332-43
references.pmid: 25754826
references.citation: Am J Psychiatry. 2010 Dec;167(12):1479-88
references.pmid: 21041246
references.citation: J Neurosci. 2010 Sep 15;30(37):12424-31
references.pmid: 20844137
references.citation: Nat Rev Neurosci. 2010 Feb;11(2):100-13
references.pmid: 20087360
references.citation: Electroencephalogr Clin Neurophysiol. 1980 Oct;50(1-2):19-24
references.pmid: 6159187
references.citation: Nature. 2013 Nov 28;503(7477):521-4
references.pmid: 24097352
references.citation: J Neurosci. 2006 May 3;26(18):4752-62
references.pmid: 16672647
references.citation: Nature. 2009 Jun 4;459(7247):698-702
references.pmid: 19396159
references.citation: JAMA Psychiatry. 2013 Jul;70(7):677-85
references.pmid: 23699867
references.citation: Prog Neuropsychopharmacol Biol Psychiatry. 2004 Mar;28(2):273-8
references.pmid: 14751422
references.citation: World Psychiatry. 2014 Oct;13(3):224-32
references.pmid: 25273286
references.citation: Biol Psychiatry. 2005 Feb 1;57(3):252-60
references.pmid: 15691526
references.citation: Neuropharmacology. 2012 Jan;62(1):42-53
references.pmid: 21889518
references.citation: J Neurosci. 2003 Jul 16;23(15):6315-26
references.pmid: 12867516
references.citation: Depress Anxiety. 2014 Oct;31(10):814-21
references.pmid: 24865448
references.citation: Mol Psychiatry. 2014 Jan;19(1):30-6
references.pmid: 24217255
references.citation: Am J Psychiatry. 2014 May;171(5):557-63
references.pmid: 24480930
references.citation: Am J Psychiatry. 2009 Apr;166(4):450-9
references.pmid: 19289452
references.citation: Biol Psychiatry. 2007 Mar 15;61(6):806-12
references.pmid: 17210135
references.citation: Nature. 2014 Jan 16;505(7483):318-26
references.pmid: 24429630
references.citation: Nat Rev Neurosci. 2005 Apr;6(4):312-24
references.pmid: 15803162
references.citation: J Neurosci. 2005 Jan 12;25(2):372-83
references.pmid: 15647480
references.citation: Int J Neuropsychopharmacol. 2011 Jul;14(6):721-34
references.pmid: 21226980
references.citation: Nat Neurosci. 2009 Jan;12(1):21-3
references.pmid: 19029887
references.citation: Science. 2013 Jan 4;339(6115):70-4
references.pmid: 23180771
references.citation: Neurobiol Learn Mem. 2005 Jan;83(1):65-71
references.pmid: 15607690
references.citation: Arch Gen Psychiatry. 1999 Nov;56(11):1043-7
references.pmid: 10565505
references.citation: Int J Neuropsychopharmacol. 2010 Sep;13(8):981-96
references.pmid: 20219156
references.citation: Nat Rev Neurosci. 2006 Sep;7(9):687-96
references.pmid: 16883309
references.citation: Arch Gen Psychiatry. 2000 Mar;57(3):237-45
references.pmid: 10711910
references.citation: Am J Psychiatry. 2015 Nov 1;172(11):1148-59
references.pmid: 26133962
references.citation: Int J Neuropsychopharmacol. 2010 May;13(4):411-20
references.pmid: 20236554
references.citation: Arch Gen Psychiatry. 1997 Apr;54(4):322-8
references.pmid: 9107148
references.citation: Trends Neurosci. 2012 Jan;35(1):57-67
references.pmid: 22154068
references.citation: Brain Behav Immun. 2013 Oct;33:190-200
references.pmid: 23876745
references.citation: Biol Psychiatry. 2013 Mar 15;73(6):574-82
references.pmid: 23140664
references.citation: J Neurosci. 2010 Jan 27;30(4):1270-87
references.pmid: 20107055
references.citation: Am J Psychiatry. 2011 Sep;168(9):921-9
references.pmid: 21632647
references.citation: J Neurosci. 2007 Oct 3;27(40):10695-702
references.pmid: 17913903
references.citation: Int J Neuropsychopharmacol. 2009 May;12(4):513-24
references.pmid: 18752727
references.citation: Front Neural Circuits. 2009 Oct 20;3:15
references.pmid: 19876404
references.citation: Cereb Cortex. 2011 May;21(5):999-1011
references.pmid: 20843900
references.citation: Arch Gen Psychiatry. 2004 Aug;61(8):774-80
references.pmid: 15289276
references.citation: Neuropharmacology. 2009 Sep;57(3):193-200
references.pmid: 19523965