title: Maternal Immune Activation Disrupts Dopamine System in the Offspring.
abstract: In utero exposure to maternal viral infections is associated with a higher incidence of psychiatric disorders with a supposed neurodevelopmental origin, including schizophrenia. Hence, immune response factors exert a negative impact on brain maturation that predisposes the offspring to the emergence of pathological phenotypes later in life. Although ventral tegmental area dopamine neurons and their target regions play essential roles in the pathophysiology of psychoses, it remains to be fully elucidated how dopamine activity and functionality are disrupted in maternal immune activation models of schizophrenia.
  
  
  
  Here, we used an immune-mediated neurodevelopmental disruption model based on prenatal administration of the polyriboinosinic-polyribocytidilic acid in rats, which mimics a viral infection and recapitulates behavioral abnormalities relevant to psychiatric disorders in the offspring. Extracellular dopamine levels were measured by brain microdialysis in both the nucleus accumbens shell and the medial prefrontal cortex, whereas dopamine neurons in ventral tegmental area were studied by in vivo electrophysiology.
  
  
  
  Polyriboinosinic-polyribocytidilic acid-treated animals, at adulthood, displayed deficits in sensorimotor gating, memory, and social interaction and increased baseline extracellular dopamine levels in the nucleus accumbens, but not in the prefrontal cortex. In polyriboinosinic-polyribocytidilic acid rats, dopamine neurons showed reduced spontaneously firing rate and population activity.
  
  
  
  These results confirm that maternal immune activation severely impairs dopamine system and that the polyriboinosinic-polyribocytidilic acid model can be considered a proper animal model of a psychiatric condition that fulfills a multidimensional set of validity criteria predictive of a human pathology.
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France.
authors.forename: Antonio
authors.initials: A
authors.lastname: Luchicchi
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Lecca
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France.
authors.forename: Miriam
authors.initials: M
authors.lastname: Melis
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France.
authors.forename: Marta
authors.initials: M
authors.lastname: De Felice
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cadeddu
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France.
authors.forename: Roberto
authors.initials: R
authors.lastname: Frau
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France.
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Muntoni
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Fadda
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France.
authors.forename: Paola
authors.initials: P
authors.lastname: Devoto
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, Monserrato, Italy (Drs Luchicchi, Lecca, Melis, Ms De Felice, Drs Cadeddu, Frau, Fadda, Devoto, and Pistis); Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy (Drs Muntoni and Pistis).Present address (A.L.): Department of Integrative Neurophysiology, Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, Vrije Universiteit, Amsterdam, Netherlands.Present address (S.L.): Institut du Fer à Moulin, 75005, Paris, France; Inserm, UMR-S 839, 75005, Paris, France. mpistis@unica.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000502:physiology*; D005260:Female; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000378:metabolism; D011070:Poly I-C / Q000276:immunology / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000276:immunology* / Q000378:metabolism*; D051381:Rats; D055139:Sensory Gating / Q000187:drug effects; D012920:Social Behavior Disorders / Q000139:chemically induced; D017557:Ventral Tegmental Area / Q000503:physiopathology; D014777:Virus Diseases / Q000276:immunology* / Q000378:metabolism*
chemical_list: D011070:Poly I-C; D004298:Dopamine
keywords: Schizophrenia; dopamine; electrophysiology; microdialysis
references.citation: Neuron. 2015 Jan 21;85(2):429-38
references.pmid: 25611513
references.citation: Brain Behav Immun. 2010 Aug;24(6):881-97
references.pmid: 20230889
references.citation: Neuropsychopharmacology. 2013 Sep;38(10):1881-8
references.pmid: 23612434
references.citation: Brain Behav. 2015 Sep 24;5(10):e00393
references.pmid: 26516613
references.citation: Psychopharmacology (Berl). 2001 Jul;156(2-3):234-58
references.pmid: 11549226
references.citation: Front Behav Neurosci. 2013 Dec 27;7:217
references.pmid: 24409130
references.citation: Transl Psychiatry. 2012 Feb 21;2:e81
references.pmid: 22832818
references.citation: Transl Psychiatry. 2014 Jul 29;4:e418
references.pmid: 25072323
references.citation: Science. 2004 Mar 26;303(5666):2040-2
references.pmid: 15044807
references.citation: J Neurosci. 2012 Jun 27;32(26):9023-34
references.pmid: 22745501
references.citation: Neuroscience. 1983 Oct;10(2):301-15
references.pmid: 6633863
references.citation: Acta Neuropathol. 1980;49(3):193-8
references.pmid: 7368897
references.citation: Neuroscience. 2008 Jun 23;154(2):701-9
references.pmid: 18495356
references.citation: Brain Behav Immun. 2015 May;46:192-202
references.pmid: 25683697
references.citation: Arch Gen Psychiatry. 1990 Feb;47(2):181-8
references.pmid: 2405807
references.citation: Synapse. 1990;6(2):207-9
references.pmid: 1978421
references.citation: Proc Natl Acad Sci U S A. 2000 Jul 5;97(14):8104-9
references.pmid: 10884434
references.citation: PLoS One. 2013;8(1):e54439
references.pmid: 23349891
references.citation: Neurosci Biobehav Rev. 2005;29(6):913-47
references.pmid: 15964075
references.citation: Behav Brain Res. 2008 Jun 26;190(1):156-9
references.pmid: 18367260
references.citation: Int J Neuropsychopharmacol. 2015 Jan 30;18(4):null
references.pmid: 25636893
references.citation: Behav Brain Res. 2004 Mar 2;149(2):159-81
references.pmid: 15129780
references.citation: J Autism Dev Disord. 2010 Dec;40(12):1423-30
references.pmid: 20414802
references.citation: Behav Brain Res. 2009 Dec 7;204(2):313-21
references.pmid: 19136031
references.citation: Am J Psychiatry. 2010 Mar;167(3):261-80
references.pmid: 20123911
references.citation: Schizophr Res. 2015 Aug;166(1-3):238-47
references.pmid: 26055633
references.citation: Neuropsychopharmacology. 2012 Apr;37(5):1164-76
references.pmid: 22169942
references.citation: Transl Psychiatry. 2013 Mar 12;3:e240
references.pmid: 23481627
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: Proc Natl Acad Sci U S A. 2003 Mar 4;100(5):2866-71
references.pmid: 12604788
references.citation: Brain Behav Immun. 2006 Jul;20(4):378-88
references.pmid: 16378711
references.citation: Behav Brain Res. 2007 Aug 6;181(2):270-7
references.pmid: 17553574
references.citation: Pediatr Res. 2011 May;69(5 Pt 2):26R-33R
references.pmid: 21289540
references.citation: J Neurosci. 2011 Jun 8;31(23):8476-90
references.pmid: 21653852
references.citation: Psychoneuroendocrinology. 2014 Jan;39:204-13
references.pmid: 24140269
references.citation: Biol Psychiatry. 2006 Mar 15;59(6):546-54
references.pmid: 16256957
references.citation: Biol Psychiatry. 2014 Feb 15;75(4):307-15
references.pmid: 23938317
references.citation: Eur Neuropsychopharmacol. 2010 Jan;20(1):25-36
references.pmid: 19854030
references.citation: J Neurosci. 2008 Dec 17;28(51):13985-94
references.pmid: 19091987
references.citation: PLoS One. 2012;7(1):e29754
references.pmid: 22238649
references.citation: Biol Psychiatry. 2015 Jun 15;77(12):1031-40
references.pmid: 25863358
references.citation: Neuropsychopharmacology. 2003 Oct;28(10):1778-89
references.pmid: 12865897
references.citation: Psychopharmacology (Berl). 2009 Jan;201(4):471-81
references.pmid: 18777018
references.citation: Int J Neuropsychopharmacol. 2013 Mar;16(2):459-70
references.pmid: 22717062
references.citation: Behav Brain Res. 2014 Jan 1;258:179-86
references.pmid: 24129217
references.citation: Curr Opin Neurobiol. 2002 Feb;12(1):115-8
references.pmid: 11861174
references.citation: Neuron. 2012 Jun 7;74(5):858-73
references.pmid: 22681690
references.citation: J Neurosci. 2010 Jan 27;30(4):1270-87
references.pmid: 20107055
references.citation: Int J Neuropsychopharmacol. 2009 May;12(4):513-24
references.pmid: 18752727
references.citation: J Neurosci. 2007 Oct 17;27(42):11424-30
references.pmid: 17942737
references.citation: J Neurosci. 2007 May 16;27(20):5414-21
references.pmid: 17507563
references.citation: Behav Brain Res. 2010 Dec 1;213(2):323-7
references.pmid: 20471999