Hyejung Won^1,2,7, Won Mah^1,2,7, Eunjin Kim¹, Jae-Won Kim³, Eun-Kyoung Hahm^1,2, Myoung-Hwan Kim^1,2, Sukhee Cho⁴, Jeongjin Kim¹, Hyeran Jang⁵, Soo-Churl Cho³, Boong-Nyun Kim³, Min-Sup Shin³, Jinsoo Seo⁴, Jaeseung Jeong⁵, Se-Young Choi⁴, Daesoo Kim¹, Changwon Kang¹ & Eunjoon Kim^{1,2,6
    
1}Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea. ²National Creative Research Initiative Center for Synaptogenesis, KAIST, Daejeon, Korea. ³Department of Child and Adolescent Psychiatry, College of Medicine, Seoul National University Hospital, Seoul, Korea. ⁴Department of Physiology, Seoul National University School of Dentistry, Seoul, Korea. ⁵Department of Bio and Brain Engineering, KAIST, Daejeon, Korea. ⁶Graduate School of Nanoscience and Technology (World Class University), KAIST, Daejeon, Korea. ⁷These authors contributed equally to this work. Correspondence should be addressed to Eunjoon Kim  or C.K.

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.