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.

Attention-Deficit/Hyperactivity Disorder–like Phenotype in a Mouse Model with Impaired Actin Dynamics

“…The neurobehavioral defects of ACC mice are very similar to defects described in ADHD mouse models, including DAT knockout or knockdown mice (4), GIT1 (G protein-coupled receptor kinase-interacting protein-1) knockout mice (31), or mice overexpressing casein kinase 1-δ (CK1δ) (27). Associative learning was impaired in DAT and GIT1 mutants (31,45), and anxiety was reduced in CK1δ-overexpressing mice (27), similar to what we reported previously for n-cofilin mutants (19,20). The behavioral abnormalities in ACC mice include all hallmarks of ADHD, suggesting that ACC mice are a valuable tool to study the mechanisms underlying ADHD.…”

“…Maintenance of the E/I balance is crucial for the functionality of the brain (49), and E/I imbalance is postulated to underlie the pathogenesis of neuropsychiatric disorders, such as autism, schizophrenia or Tourette's syndrome (50)(51)(52). More recent studies have associated E/I imbalance with ADHD (31,(53)(54)(55). In these studies, it is suggested that reduced neuronal inhibition contributes to ADHD pathogenesis.…”

“…The dopamine/norepinephrine reuptake inhibitor methylphenidate is widely used for ADHD treatment and normalizes locomotion in ADHD mouse models (1,4,27,30,31). We analyzed whether methylphenidate has similar effects in ACC mice.…”

Expanding functions of GIT Arf GTPase-activating proteins, PIX Rho guanine nucleotide exchange factors and GIT–PIX complexes

“…Pulldown of GIT or PIX quantitatively captures the other partner . GIT and PIX appear unstable when not in a complex because T-cells of α-PIX-deficient mice have reduced levels of GIT2 (Missy et al, 2008), GIT1-deficient mice have reduced levels of PIX in the brain (Won et al, 2011) and GIT2-deficient mice have reduced levels of PIX in immune organs (Hao et al, 2015). Nevertheless, despite clear evidence that GIT and PIX are tightly associated and function together, many publications continue to report on GIT or PIX proteins individually, ignoring potential involvement of the other partner.…”

The Adaptor Protein and Arf GTPase-activating Protein Cat-1/Git-1 Is Required for Cellular Transformation

“…Indeed, Cat-1 has recently been implicated in stimulating neuronal synaptic activity (11) and dendritic spine formation (12,13), as well as in inducing T-cell activation (14). Moreover, Cat-1 has been implicated in attention deficit hyperactivity disorder and in Huntington disease (15,16).…”