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

• Published in: Cell reports (Cambridge) Vol. 16; no. 8; pp. 2116 - 2128
• Main Authors: Managò, Francesca, Mereu, Maddalena, Mastwal, Surjeet, Mastrogiacomo, Rosa, Scheggia, Diego, Emanuele, Marco, De Luca, Maria A., Weinberger, Daniel R., Wang, Kuan Hong, Papaleo, Francesco
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.08.2016; Elsevier
• Subjects: 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology; Amphetamine - pharmacology; Animals; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - physiopathology; Cognitive Dysfunction - prevention & control; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Corpus Striatum - physiopathology; Cytoskeletal Proteins - deficiency; Cytoskeletal Proteins - genetics; Disease Models, Animal; Dopamine - metabolism; Dopamine Agonists - pharmacology; Dopamine Antagonists - pharmacology; Female; Gene Expression; Male; Mice; Mice, Knockout; Nerve Tissue Proteins - deficiency; Nerve Tissue Proteins - genetics; Phenotype; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Prefrontal Cortex - physiopathology; Psychomotor Disorders - genetics; Psychomotor Disorders - metabolism; Psychomotor Disorders - physiopathology; Psychomotor Disorders - prevention & control; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Salicylamides - pharmacology; Schizophrenia - genetics; Schizophrenia - metabolism; Schizophrenia - physiopathology; Schizophrenia - prevention & control; Sensory Gating - drug effects; Sensory Gating - genetics; Synaptic Transmission
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.07.044

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. [Display omitted] •Arc genetic disruption recapitulates schizophrenia-relevant behavioral abnormalities•Arc disruption leads to hypoactive PFC dopamine (DA) and hyperactive striatal DA system•Hypo-PFC and hyper-striatal DA mediates cognitive and motor changes, respectively•Arc is a convergence point for genes implicated in schizophrenia risk Managò et al. 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.