Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia

Francesca Managò, Maddalena Mereu, Surjeet Mastwal, Rosa Mastrogiacomo, Diego Scheggia, Marco Emanuele, Maria A. De Luca, Daniel R. Weinberger, Kuan Hong Wang, Francesco Papaleo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2116-2128
Number of pages13
JournalCell Reports
Volume16
Issue number8
DOIs
StatePublished - Aug 23 2016

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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