title: Loss-of-function of PTPR γ and ζ, observed in sporadic schizophrenia, causes brain region-specific deregulation of monoamine levels and altered behavior in mice.
abstract: The receptor protein tyrosine phosphatase PTPRG has been genetically associated with psychiatric disorders and is a ligand for members of the contactin family, which are themselves linked to autism spectrum disorders.
  
  
  
  Based on our finding of a phosphatase-null de novo mutation in PTPRG associated with a case of sporadic schizophrenia, we used PTPRG knockout (KO) mice to model the effect of a loss-of-function mutation. We compared the results with loss-of-function in its close paralogue PTPRZ, previously associated with schizophrenia. We tested PTPRG-/-, PTPRZ-/-, and wild-type male mice for effects on social behavior, forced swim test, and anxiety, as well as on regional brain neurochemistry.
  
  
  
  The most notable behavioral consequences of PTPRG gene inactivation were reduced immobilization in the forced swim test, suggestive of some negative symptoms of schizophrenia. By contrast, PTPRZ-/-mice demonstrated marked social alteration with increased aggressivity, reminiscent of some positive symptoms of schizophrenia. Both knockouts showed elevated dopamine levels in prefrontal cortex, hippocampus, and most particularly amygdala, but not striatum, accompanied by reduced dopamine beta hydroxylase activity only in amygdala. In addition, PTPRG KO elicited a distinct increase in hippocampal serotonin level not observed in PTPRZ KO.
  
  
  
  PTPRG and PTPRZ gene loss therefore induces distinct patterns of behavioral change and region-specific alterations in neurotransmitters, highlighting their usefulness as models for neuropsychiatric disorder mechanisms and making these receptors attractive targets for therapy.
authors.affiliation: Neurobiologie de la prise de décision, Paris-Saclay Institute of Neuroscience (Neuro-PSI), CNRS UMR 9197 and Université Paris Sud, Orsay, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Cressant
authors.affiliation: Department of Neuroscience, Institut Pasteur, 75724, Paris, France.|Université Paris 7 Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Dubreuil
authors.affiliation: Department of Neuroscience, Institut Pasteur, 75724, Paris, France.
authors.forename: Jing
authors.initials: J
authors.lastname: Kong
authors.affiliation: Department of psychiatry, New York University Langone School of Medicine, New York, NY, 10016, USA.
authors.forename: Thorsten Manfred
authors.initials: TM
authors.lastname: Kranz
authors.affiliation: Institut Pasteur, URA 2182, 75015, Paris, France.
authors.forename: Francoise
authors.initials: F
authors.lastname: Lazarini
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire Hôpital Lariboisière, INSERM U942, 75010, Paris, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Launay
authors.affiliation: Laboratoire de Biochimie et Biologie Moléculaire Hôpital Lariboisière, INSERM U942, 75010, Paris, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Callebert
authors.affiliation: Université Paris 7 Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Jan
authors.initials: J
authors.lastname: Sap
authors.affiliation: Department of psychiatry, New York University Langone School of Medicine, New York, NY, 10016, USA.
authors.forename: Dolores
authors.initials: D
authors.lastname: Malaspina
authors.affiliation: Neurobiologie de la prise de décision, Paris-Saclay Institute of Neuroscience (Neuro-PSI), CNRS UMR 9197 and Université Paris Sud, Orsay, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Granon
authors.affiliation: Department of Neuroscience, Institut Pasteur, 75724, Paris, France. Harrochsheila@gmail.com.|Department of psychiatry, New York University Langone School of Medicine, New York, NY, 10016, USA. Harrochsheila@gmail.com.
authors.forename: Sheila
authors.initials: S
authors.lastname: Harroch
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D012919:Social Behavior; D013550:Swimming
chemical_list: D012701:Serotonin; C516851:Ptprg protein, mouse; C516896:Ptprz1 protein, mouse; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5; D004298:Dopamine
keywords: Aggression; Anxiety; Contactins; Mental disorders; Phosphatase; Social behavior