title: GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice.
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.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Hyejung
authors.initials: H
authors.lastname: Won
authors.forename: Won
authors.initials: W
authors.lastname: Mah
authors.forename: Eunjin
authors.initials: E
authors.lastname: Kim
authors.forename: Jae-Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Hahm
authors.forename: Myoung-Hwan
authors.initials: MH
authors.lastname: Kim
authors.forename: Sukhee
authors.initials: S
authors.lastname: Cho
authors.forename: Jeongjin
authors.initials: J
authors.lastname: Kim
authors.forename: Hyeran
authors.initials: H
authors.lastname: Jang
authors.forename: Soo-Churl
authors.initials: SC
authors.lastname: Cho
authors.forename: Boong-Nyun
authors.initials: BN
authors.lastname: Kim
authors.forename: Min-Sup
authors.initials: MS
authors.lastname: Shin
authors.forename: Jinsoo
authors.initials: J
authors.lastname: Seo
authors.forename: Jaeseung
authors.initials: J
authors.lastname: Jeong
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Choi
authors.forename: Daesoo
authors.initials: D
authors.lastname: Kim
authors.forename: Changwon
authors.initials: C
authors.lastname: Kang
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000502:physiology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology; D001921:Brain / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002648:Child; D004195:Disease Models, Animal; D004569:Electroencephalography; D005260:Female; D020690:GTPase-Activating Proteins / Q000172:deficiency* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000235:genetics / Q000523:psychology; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction; D009435:Synaptic Transmission; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D000697:Central Nervous System Stimulants; C485647:GIT1 protein, human; D020690:GTPase-Activating Proteins; C120766:Git1 protein, mouse; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D008774:Methylphenidate; D000661:Amphetamine; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein