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Cell Rep. 2016 Aug 23;16(8):2116-2128. doi: 10.1016/j.celrep.2016.07.044. Epub 2016 Aug 11.

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

Author information

1
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy.
2
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Largo Meneghetti 2, 35131 Padova, Italy.
3
Unit on Neural Circuits and Adaptive Behaviors, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Bethesda, MD 20892, USA.
4
Department of Biomedical Sciences, Università di Cagliari, 09124 Cagliari, Italy.
5
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.
6
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.
7
Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy. Electronic address: francesco.papaleo@iit.it.

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.

PMID:
27524619
PMCID:
PMC5001893
DOI:
10.1016/j.celrep.2016.07.044
[Indexed for MEDLINE]
Free PMC Article

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