Abstract
Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder that affects ~5% of school-aged children; however, the mechanisms underlying ADHD remain largely unclear. Here we report a previously unidentified association between G protein-coupled receptor kinase-interacting protein-1 (GIT1) and ADHD in humans. An intronic single-nucleotide polymorphism in GIT1, the minor allele of which causes reduced GIT1 expression, shows a strong association with ADHD susceptibility in humans. Git1-deficient mice show ADHD-like phenotypes, with traits including hyperactivity, enhanced electroencephalogram theta rhythms and impaired learning and memory. Hyperactivity in Git1(-/-) mice is reversed by amphetamine and methylphenidate, psychostimulants commonly used to treat ADHD. In addition, amphetamine normalizes enhanced theta rhythms and impaired memory. GIT1 deficiency in mice leads to decreases in ras-related C3 botulinum toxin substrate-1 (RAC1) signaling and inhibitory presynaptic input; furthermore, it shifts the neuronal excitation-inhibition balance in postsynaptic neurons toward excitation. Our study identifies a previously unknown involvement of GIT1 in human ADHD and shows that GIT1 deficiency in mice causes psychostimulant-responsive ADHD-like phenotypes.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics*
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Adaptor Proteins, Signal Transducing / physiology
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Amphetamine / pharmacology
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Animals
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Attention Deficit Disorder with Hyperactivity / drug therapy
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Attention Deficit Disorder with Hyperactivity / genetics*
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Attention Deficit Disorder with Hyperactivity / physiopathology
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Attention Deficit Disorder with Hyperactivity / psychology
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Brain / physiopathology
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Cell Cycle Proteins / genetics*
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Cell Cycle Proteins / physiology
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Central Nervous System Stimulants / pharmacology
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Child
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Disease Models, Animal
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Electroencephalography
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Female
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GTPase-Activating Proteins / deficiency*
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GTPase-Activating Proteins / genetics*
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Genetic Predisposition to Disease
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Humans
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Male
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Memory Disorders / drug therapy
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Memory Disorders / genetics
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Memory Disorders / psychology
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Methylphenidate / pharmacology
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Mice
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Mice, Knockout
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Motor Activity / drug effects
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Motor Activity / genetics
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Motor Activity / physiology
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Neuropeptides / metabolism
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Phenotype
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Polymorphism, Single Nucleotide
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Signal Transduction
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Synaptic Transmission
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rac GTP-Binding Proteins / metabolism
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rac1 GTP-Binding Protein
Substances
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Central Nervous System Stimulants
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GIT1 protein, human
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GTPase-Activating Proteins
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Git1 protein, mouse
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Neuropeptides
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Rac1 protein, mouse
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Methylphenidate
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Amphetamine
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rac GTP-Binding Proteins
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rac1 GTP-Binding Protein