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

ADHD is characterized by hyperactivity and deficits in learning and memory. Now, Eunjoon Kim and colleagues report that a polymorphism in the gene that encodes the adaptor protein GIT1 is linked to ADHD in humans. This polymorphism reduces GIT1 expression, and GIT1-deficient mice show ADHD-like behaviors that can be alleviated with the psychostimulant drugs used to treat human ADHD. 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.