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
Affiliations
Francesca Managò
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
Maddalena Mereu
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Largo Meneghetti 2, 35131 Padova, Italy
Surjeet Mastwal
Unit on Neural Circuits and Adaptive Behaviors, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892, USA
Rosa Mastrogiacomo
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
Diego Scheggia
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
Marco Emanuele
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
Maria A. De Luca
Department of Biomedical Sciences, Università di Cagliari, 09124 Cagliari, Italy
Daniel R. Weinberger
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD 21205, USA
Kuan Hong Wang
Unit on Neural Circuits and Adaptive Behaviors, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892, USA
Francesco Papaleo
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
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.
