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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.

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Figure 1: Hyperactivity and impaired memory in Git1−/− mice are normalized by amphetamine treatment.
Figure 2: Enhanced theta rhythms in the frontal cortex of Git1−/− mice are reduced by amphetamine.
Figure 3: Suppressed GIT1-PIX-RAC1-PAK signaling in the Git1−/− brain.
Figure 4: Reduced inhibitory transmission and elevated excitatory transmission at Git1−/− synapses.
Figure 5: Reduced presynaptic input at Git1−/− inhibitory synapses.

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Acknowledgements

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 (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.).

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Authors

Contributions

Eunjin K. conducted the SNP experiments; J.-W.K., S.-C.C., B.-N.K. and M.-S.S. provided the ADHD and control samples and conducted clinical data analyses; E.-K.H. generated Git1−/− mice; M.-H.K. measured and analyzed minicurrents; S.C., J.S. and S.-Y.C. measured and analyzed evoked synaptic transmission; J.K., H.J. and J.J. contributed to EEG recordings; H.W. and W.M. conducted all the rest of the experiments; D.K., C.K. and Eunjoon K. supervised the project and wrote the manuscript.

Corresponding authors

Correspondence to Changwon Kang or Eunjoon Kim.

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The authors declare no competing financial interests.

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Won, H., Mah, W., Kim, E. et al. GIT1 is associated with ADHD in humans and ADHD-like behaviors in mice. Nat Med 17, 566–572 (2011). https://doi.org/10.1038/nm.2330

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