GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice

Hyejung Won, Won Mah, Eunjin Kim, Jae Won Kim, Eun Kyoung Hahm, Myoung Hwan Kim, Sukhee Cho, Jeongjin Kim, Hyeran Jang, Soo Churl Cho, Boong Nyun Kim, Min Sup Shin, Jinsoo Seo, Jaeseung Jeong, Se Young Choi, Daesoo Kim, Changwon Kang, Eunjoon Kim

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

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 proteing-coupled receptor kinaseg-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.

Original languageEnglish
Pages (from-to)566-572
Number of pages7
JournalNature Medicine
Volume17
Issue number5
DOIs
StatePublished - May 2011

Bibliographical note

Funding Information:
(2010-0014162 to C.K. and 313-2007-2-C00630 to S.-Y.C.), the Basic Science Program through the National Research Foundation of Korea (2010-0002283 to J.K.), the Mid-career Researcher Program through the National Research Foundation of Korea (20100000032 to D.K.), the Seoul National University Hospital Research Fund (09-2008-001-0 to J.K.) and by a T.J. Park Doctoral Fellowship (to H.W.).

Funding Information:
We thank the Vector Integration Site Analysis service at the University of California–Davis Mouse Biology Program for providing the data on the single-copy status of the Git1 gene trap. This work was supported by the Korean National Creative Research Initiative program and WCU (World Class University) program (R31-2008-000-10071-0) funded by the Ministry of Education, Science, and Technology (to Eunjoon K.), the National Research Foundation of Korea

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