Abstract
Autism is a developmental disorder of the nervous system associated with impaired social communication and interactions as well excessive repetitive behaviors. There are no drug therapies that directly target the pathology of this disease. The retinoic acid receptor-related orphan receptor α (RORα) is a nuclear receptor that has been demonstrated to have reduced expression in many individuals with autism spectrum disorder (ASD). Several genes that have been shown to be downregulated in individuals with ASD have also been identified as putative RORα target genes. Utilizing a synthetic RORα/γ agonist, SR1078, that we identified previously, we demonstrate that treatment of BTBR mice (a model of autism) with SR1078 results in reduced repetitive behavior. Furthermore, these mice display increased expression of ASD-associated RORα target genes in both the brains of the BTBR mice and in a human neuroblastoma cell line treated with SR1078. These data suggest that pharmacological activation of RORα may be a method for treatment of autism.
Keywords:
Autism; behavior; drug discovery; nuclear receptor; orphan receptor.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Ataxin-2 / genetics
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Ataxin-2 / metabolism
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Autism Spectrum Disorder / complications
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Autism Spectrum Disorder / drug therapy*
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Autism Spectrum Disorder / genetics
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Autophagy-Related Protein-1 Homolog / genetics
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Benzamides / therapeutic use*
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Brain / drug effects
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Brain / metabolism
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Cell Adhesion Molecules, Neuronal / genetics
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Cell Adhesion Molecules, Neuronal / metabolism
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Cell Line, Tumor
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Gene Expression Regulation / drug effects*
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Grooming / drug effects
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HEK293 Cells
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Humans
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Inositol 1,4,5-Trisphosphate Receptors / genetics
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Inositol 1,4,5-Trisphosphate Receptors / metabolism
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Intracellular Signaling Peptides and Proteins / genetics
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L-Lactate Dehydrogenase / genetics
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L-Lactate Dehydrogenase / metabolism
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Mice
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Mice, Inbred Strains
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Neuroblastoma / pathology
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Nuclear Receptor Subfamily 1, Group F, Member 1 / agonists*
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Nuclear Receptor Subfamily 1, Group F, Member 1 / genetics
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Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism*
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REM Sleep Behavior Disorder / drug therapy
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REM Sleep Behavior Disorder / etiology
Substances
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ATXN2 protein, human
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Ataxin-2
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Benzamides
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Cell Adhesion Molecules, Neuronal
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Inositol 1,4,5-Trisphosphate Receptors
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Intracellular Signaling Peptides and Proteins
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Nuclear Receptor Subfamily 1, Group F, Member 1
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SR 1078
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neuroligin 1
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L-Lactate Dehydrogenase
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Autophagy-Related Protein-1 Homolog
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ULK1 protein, human