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.
Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, N.I.H., Intramural
MeSH terms
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2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
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Amphetamine / pharmacology
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Animals
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Cognitive Dysfunction / genetics*
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Cognitive Dysfunction / metabolism
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Cognitive Dysfunction / physiopathology
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Cognitive Dysfunction / prevention & control
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Corpus Striatum / drug effects
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Corpus Striatum / metabolism
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Corpus Striatum / physiopathology
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Cytoskeletal Proteins / deficiency
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Cytoskeletal Proteins / genetics*
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Disease Models, Animal
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Dopamine / metabolism*
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Dopamine Agonists / pharmacology
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Dopamine Antagonists / pharmacology
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Female
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Gene Expression
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Male
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Mice
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Mice, Knockout
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics*
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Phenotype
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Prefrontal Cortex / drug effects
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Prefrontal Cortex / metabolism
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Prefrontal Cortex / physiopathology
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Psychomotor Disorders / genetics*
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Psychomotor Disorders / metabolism
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Psychomotor Disorders / physiopathology
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Psychomotor Disorders / prevention & control
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Receptors, Dopamine D1 / genetics
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Receptors, Dopamine D1 / metabolism
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Receptors, Dopamine D2 / genetics
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Receptors, Dopamine D2 / metabolism
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Salicylamides / pharmacology
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Schizophrenia / genetics*
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Schizophrenia / metabolism
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Schizophrenia / physiopathology
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Schizophrenia / prevention & control
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Sensory Gating / drug effects
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Sensory Gating / genetics
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Synaptic Transmission
Substances
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Cytoskeletal Proteins
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Dopamine Agonists
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Dopamine Antagonists
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Nerve Tissue Proteins
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Receptors, Dopamine D1
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Receptors, Dopamine D2
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Salicylamides
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activity regulated cytoskeletal-associated protein
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2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
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Amphetamine
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eticlopride
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Dopamine