title: Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and 'Schizophrenia-Like Behaviors' in Mice.
abstract: Rasd2 is a thyroid hormone target gene, which encodes for a GTP-binding protein enriched in the striatum where, among other functions, it modulates dopaminergic neurotransmission. Here we report that human RASD2 mRNA is abundant in putamen, but it also occurs in the cerebral cortex, with a distinctive expression pattern that differs from that present in rodents. Consistent with its localization, we found that a genetic variation in RASD2 (rs6518956) affects postmortem prefrontal mRNA expression in healthy humans and is associated with phenotypes of relevance to schizophrenia, including prefrontal and striatal grey matter volume and physiology during working memory, as measured with magnetic resonance imaging. Interestingly, quantitative real-time PCR analysis indicated that RASD2 mRNA is slightly reduced in postmortem prefrontal cortex of patients with schizophrenia. In the attempt to uncover the neurobiological substrates associated with Rasd2 activity, we used knockout mice to analyze the in vivo influence of this G-protein on the prepulse inhibition of the startle response and psychotomimetic drug-related behavioral response. Data showed that Rasd2 mutants display deficits in basal prepulse inhibition that, in turn, exacerbate gating disruption under psychotomimetic drug challenge. Furthermore, we documented that lack of Rasd2 strikingly enhances the behavioral sensitivity to motor stimulation elicited by amphetamine and phencyclidine. Based on animal model data, along with the finding that RASD2 influences prefronto-striatal phenotypes in healthy humans, we suggest that genetic mutation or reduced levels of this G-protein might have a role in cerebral circuitry dysfunction underpinning exaggerated psychotomimetic drugs responses and development of specific biological phenotypes linked to schizophrenia.
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.|Dipartimento di Scienze Motorie e del Benessere DiSMeB, Università degli Studi di Napoli Parthenope, Naples, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Vitucci
authors.affiliation: Istituto di Ricovero e Cura a Carattere Scientifico 'Casa Sollievo della Sofferenza', Foggia, Italy.
authors.forename: Annabella
authors.initials: A
authors.lastname: Di Giorgio
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Napolitano
authors.affiliation: Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pelosi
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.|Department of Molecular Medicine and Medical Biotechnology, University of Naples 'Federico II', Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Errico
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Attrotto
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gelao
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Fazio
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Taurisano
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Di Maio
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Marsili
authors.affiliation: Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, Pisa, Italy.|Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems, Rovereto (Trento), Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pasqualetti
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari 'Aldo Moro', Bari, Italy.|pRED, Neuroscience DTA, Hoffmann-La Roche, Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
authors.affiliation: Ceinge Biotecnologie Avanzate, Naples, Italy.|Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, Second University of Naples (SUN), Caserta, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Usiello
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012565:Schizophrenic Psychology
chemical_list: D012333:RNA, Messenger; D019204:GTP-Binding Proteins; C486702:RASD2 protein, human; C488189:Rasd2 protein, mouse