title: Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia.
abstract: Human genetic studies have recently suggested that the postsynaptic activity-regulated cytoskeleton-associated protein (Arc) complex is a convergence signal for several genes implicated in schizophrenia. However, the functional significance of Arc in schizophrenia-related neurobehavioral phenotypes and brain circuits is unclear. Here, we find that, consistent with schizophrenia-related phenotypes, disruption of Arc in mice produces deficits in sensorimotor gating, cognitive functions, social behaviors, and amphetamine-induced psychomotor responses. Furthermore, genetic disruption of Arc leads to concomitant hypoactive mesocortical and hyperactive mesostriatal dopamine pathways. Application of a D1 agonist to the prefrontal cortex or a D2 antagonist in the ventral striatum rescues Arc-dependent cognitive or psychomotor abnormalities, respectively. Our findings demonstrate a role for Arc in the regulation of dopaminergic neurotransmission and related behaviors. The results also provide initial biological support implicating Arc in dopaminergic and behavioral abnormalities related to schizophrenia.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Managò
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Largo Meneghetti 2, 35131 Padova, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Mereu
authors.affiliation: Unit on Neural Circuits and Adaptive Behaviors, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892, USA.
authors.forename: Surjeet
authors.initials: S
authors.lastname: Mastwal
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
authors.forename: Rosa
authors.initials: R
authors.lastname: Mastrogiacomo
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Scheggia
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Emanuele
authors.affiliation: Department of Biomedical Sciences, Università di Cagliari, 09124 Cagliari, Italy.
authors.forename: Maria A
authors.initials: MA
authors.lastname: De Luca
authors.affiliation: Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD 21205, USA; Departments of Psychiatry, Neurology, and Neuroscience and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.affiliation: Unit on Neural Circuits and Adaptive Behaviors, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892, USA. Electronic address: wkuan@mail.nih.gov.
authors.forename: Kuan Hong
authors.initials: KH
authors.lastname: Wang
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy. Electronic address: francesco.papaleo@iit.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Papaleo
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D010641:Phenotype; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011596:Psychomotor Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D012457:Salicylamides / Q000494:pharmacology; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D055139:Sensory Gating / Q000187:drug effects / Q000235:genetics; D009435:Synaptic Transmission
chemical_list: D003598:Cytoskeletal Proteins; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D009419:Nerve Tissue Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C092069:activity regulated cytoskeletal-associated protein; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000661:Amphetamine; C045989:eticlopride; D004298:Dopamine