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

Nature Medicine volume 17, pages 566–572 (2011)Cite this article

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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.

References

  1. Barkley, R.A. Attention deficit hyperactivity disorder. A Handbook for Diagnosis and Treatment. 3rd ed. (Guilford, New York, 2006).

    Google Scholar 

  2. Swanson, J.M. et al. Etiologic subtypes of attention-deficit/hyperactivity disorder: brain imaging, molecular genetic and environmental factors and the dopamine hypothesis. Neuropsychol. Rev. 17, 39–59 (2007).

    Article  Google Scholar 

  3. Bakker, S.C. et al. A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am. J. Hum. Genet. 72, 1251–1260 (2003).

    Article  CAS  Google Scholar 

  4. Fisher, S.E. et al. A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am. J. Hum. Genet. 70, 1183–1196 (2002).

    Article  CAS  Google Scholar 

  5. Ogdie, M.N. et al. Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11. Am. J. Hum. Genet. 75, 661–668 (2004).

    Article  CAS  Google Scholar 

  6. Ogdie, M.N. et al. A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am. J. Hum. Genet. 72, 1268–1279 (2003).

    Article  CAS  Google Scholar 

  7. Zhou, K. et al. Meta-analysis of genome-wide linkage scans of attention deficit hyperactivity disorder. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 147B, 1392–1398 (2008).

    Article  CAS  Google Scholar 

  8. Arcos-Burgos, M. et al. Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am. J. Hum. Genet. 75, 998–1014 (2004).

    Article  CAS  Google Scholar 

  9. Franke, B., Neale, B.M. & Faraone, S.V. Genome-wide association studies in ADHD. Hum. Genet. 126, 13–50 (2009).

    Article  CAS  Google Scholar 

  10. Premont, R.T. et al. beta2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein. Proc. Natl. Acad. Sci. USA 95, 14082–14087 (1998).

    Article  CAS  Google Scholar 

  11. Claing, A. et al. Multiple endocytic pathways of G protein-coupled receptors delineated by GIT1 sensitivity. Proc. Natl. Acad. Sci. USA 97, 1119–1124 (2000).

    Article  CAS  Google Scholar 

  12. Hoefen, R.J. & Berk, B.C. The multifunctional GIT family of proteins. J. Cell Sci. 119, 1469–1475 (2006).

    Article  CAS  Google Scholar 

  13. Albertinazzi, C., Za, L., Paris, S. & de Curtis, I. ADP-ribosylation factor 6 and a functional PIX/p95–APP1 complex are required for Rac1B-mediated neurite outgrowth. Mol. Biol. Cell 14, 1295–1307 (2003).

    Article  CAS  Google Scholar 

  14. Za, L. et al. betaPIX controls cell motility and neurite extension by regulating the distribution of GIT1. J. Cell Sci. 119, 2654–2666 (2006).

    Article  CAS  Google Scholar 

  15. Segura, I., Essmann, C.L., Weinges, S. & Acker-Palmer, A. Grb4 and GIT1 transduce ephrinB reverse signals modulating spine morphogenesis and synapse formation. Nat. Neurosci. 10, 301–310 (2007).

    Article  CAS  Google Scholar 

  16. Zhang, H., Webb, D.J., Asmussen, H., Niu, S. & Horwitz, A.F.A. GIT1/PIX/Rac/PAK signaling module regulates spine morphogenesis and synapse formation through MLC. J. Neurosci. 25, 3379–3388 (2005).

    Article  CAS  Google Scholar 

  17. Zhang, H., Webb, D.J., Asmussen, H. & Horwitz, A.F. Synapse formation is regulated by the signaling adaptor GIT1. J. Cell Biol. 161, 131–142 (2003).

    Article  CAS  Google Scholar 

  18. Menon, P. et al. Impaired spine formation and learning in GPCR kinase 2 interacting protein-1 (GIT1) knockout mice. Brain Res. 1317, 218–226 (2010).

    Article  CAS  Google Scholar 

  19. Saneyoshi, T. et al. Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex. Neuron 57, 94–107 (2008).

    Article  CAS  Google Scholar 

  20. Kim, S. et al. The GIT family of proteins forms multimers and associates with the presynaptic cytomatrix protein Piccolo. J. Biol. Chem. 278, 6291–6300 (2003).

    Article  CAS  Google Scholar 

  21. Ko, J. et al. Interaction between liprin-alpha and GIT1 is required for AMPA receptor targeting. J. Neurosci. 23, 1667–1677 (2003).

    Article  CAS  Google Scholar 

  22. Schmalzigaug, R. et al. Impaired fear response in mice lacking GIT1. Neurosci. Lett. 458, 79–83 (2009).

    Article  CAS  Google Scholar 

  23. Goehler, H. et al. A protein interaction network links GIT1, an enhancer of huntingtin aggregation, to Huntington's disease. Mol. Cell 15, 853–865 (2004).

    Article  CAS  Google Scholar 

  24. Barkley, R.A. Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychol. Bull. 121, 65–94 (1997).

    Article  Google Scholar 

  25. Gilden, D.L. & Hancock, H. Response variability in attention-deficit disorders. Psychol. Sci. 18, 796–802 (2007).

    Article  Google Scholar 

  26. Castellanos, F.X. & Tannock, R. Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat. Rev. Neurosci. 3, 617–628 (2002).

    Article  CAS  Google Scholar 

  27. Russell, V.A. Reprint of “Neurobiology of animal models of attention-deficit hyperactivity disorder.” J. Neurosci. Methods 166, I–XIV (2007).

    Article  Google Scholar 

  28. Gainetdinov, R.R. et al. Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science 283, 397–401 (1999).

    Article  CAS  Google Scholar 

  29. Hess, E.J., Collins, K.A. & Wilson, M.C. Mouse model of hyperkinesis implicates SNAP-25 in behavioral regulation. J. Neurosci. 16, 3104–3111 (1996).

    Article  CAS  Google Scholar 

  30. Barry, R.J., Clarke, A.R. & Johnstone, S.J. A review of electrophysiology in attention-deficit/hyperactivity disorder: I. Qualitative and quantitative electroencephalography. Clin. Neurophysiol. 114, 171–183 (2003).

    Article  Google Scholar 

  31. Düzel, E., Penny, W.D. & Burgess, N. Brain oscillations and memory. Curr. Opin. Neurobiol. 20, 143–149 (2010).

    Article  Google Scholar 

  32. Uhlhaas, P.J. & Singer, W. Abnormal neural oscillations and synchrony in schizophrenia. Nat. Rev. Neurosci. 11, 100–113 (2010).

    Article  CAS  Google Scholar 

  33. Clarke, A.R., Barry, R.J., Bond, D., McCarthy, R. & Selikowitz, M. Effects of stimulant medications on the EEG of children with attention-deficit/hyperactivity disorder. Psychopharmacology (Berl.) 164, 277–284 (2002).

    Article  CAS  Google Scholar 

  34. Feng, Q., Albeck, J.G., Cerione, R.A. & Yang, W. Regulation of the Cool/Pix proteins: key binding partners of the Cdc42/Rac targets, the p21-activated kinases. J. Biol. Chem. 277, 5644–5650 (2002).

    Article  CAS  Google Scholar 

  35. Chavrier, P. & Goud, B. The role of ARF and Rab GTPases in membrane transport. Curr. Opin. Cell Biol. 11, 466–475 (1999).

    Article  CAS  Google Scholar 

  36. Donaldson, J.G. Multiple roles for Arf6: sorting, structuring, and signaling at the plasma membrane. J. Biol. Chem. 278, 41573–41576 (2003).

    Article  CAS  Google Scholar 

  37. Daly, G., Hawi, Z., Fitzgerald, M. & Gill, M. Mapping susceptibility loci in attention deficit hyperactivity disorder: preferential transmission of parental alleles at DAT1, DBH and DRD5 to affected children. Mol. Psychiatry 4, 192–196 (1999).

    Article  CAS  Google Scholar 

  38. LaHoste, G.J. et al. Dopamine D4 receptor gene polymorphism is associated with attention deficit hyperactivity disorder. Mol. Psychiatry 1, 121–124 (1996).

    CAS  PubMed  Google Scholar 

  39. Bokoch, G.M. Biology of the p21-activated kinases. Annu. Rev. Biochem. 72, 743–781 (2003).

    Article  CAS  Google Scholar 

  40. Boda, B., Nikonenko, I., Alberi, S. & Muller, D. Central nervous system functions of PAK protein family: from spine morphogenesis to mental retardation. Mol. Neurobiol. 34, 67–80 (2006).

    Article  CAS  Google Scholar 

  41. Meyer, D.K. et al. Regulation of somatodendritic GABAA receptor channels in rat hippocampal neurons: evidence for a role of the small GTPase Rac1. J. Neurosci. 20, 6743–6751 (2000).

    Article  CAS  Google Scholar 

  42. Cobos, I., Borello, U. & Rubenstein, J.L. Dlx transcription factors promote migration through repression of axon and dendrite growth. Neuron 54, 873–888 (2007).

    Article  CAS  Google Scholar 

  43. Richter, K. et al. Presynaptic cytomatrix protein bassoon is localized at both excitatory and inhibitory synapses of rat brain. J. Comp. Neurol. 408, 437–448 (1999).

    Article  CAS  Google Scholar 

  44. Barkley, R.A. A review of stimulant drug research with hyperactive children. J. Child Psychol. Psychiatry 18, 137–165 (1977).

    Article  CAS  Google Scholar 

  45. Rosa-Neto, P. et al. Methylphenidate-evoked changes in striatal dopamine correlate with inattention and impulsivity in adolescents with attention deficit hyperactivity disorder. Neuroimage 25, 868–876 (2005).

    Article  Google Scholar 

  46. Südhof, T.C. Neuroligins and neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008).

    Article  Google Scholar 

  47. Tabuchi, K. et al. A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318, 71–76 (2007).

    Article  CAS  Google Scholar 

  48. Deutsch, S.I., Rosse, R.B., Schwartz, B.L. & Mastropaolo, J. A revised excitotoxic hypothesis of schizophrenia: therapeutic implications. Clin. Neuropharmacol. 24, 43–49 (2001).

    Article  CAS  Google Scholar 

  49. Fernandez, F. et al. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat. Neurosci. 10, 411–413 (2007).

    Article  CAS  Google Scholar 

  50. Kleschevnikov, A.M. et al. Hippocampal long-term potentiation suppressed by increased inhibition in the Ts65Dn mouse, a genetic model of Down syndrome. J. Neurosci. 24, 8153–8160 (2004).

    Article  CAS  Google Scholar 

  51. Costa, R.M. et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 415, 526–530 (2002).

    Article  CAS  Google Scholar 

  52. Cui, Y. et al. Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135, 549–560 (2008).

    Article  CAS  Google Scholar 

  53. Shilyansky, C. et al. Neurofibromin regulates corticostriatal inhibitory networks during working memory performance. Proc. Natl. Acad. Sci. USA 107, 13141–13146 (2010).

    Article  CAS  Google Scholar 

  54. Kalanithi, P.S. et al. Altered parvalbumin-positive neuron distribution in basal ganglia of individuals with Tourette syndrome. Proc. Natl. Acad. Sci. USA 102, 13307–13312 (2005).

    Article  CAS  Google Scholar 

  55. Moll, G.H., Heinrich, H. & Rothenberger, A. Methylphenidate and intracortical excitability: opposite effects in healthy subjects and attention-deficit hyperactivity disorder. Acta Psychiatr. Scand. 107, 69–72 (2003).

    Article  CAS  Google Scholar 

  56. Moll, G.H., Heinrich, H., Trott, G., Wirth, S. & Rothenberger, A. Deficient intracortical inhibition in drug-naive children with attention-deficit hyperactivity disorder is enhanced by methylphenidate. Neurosci. Lett. 284, 121–125 (2000).

    Article  CAS  Google Scholar 

  57. Richter, M.M., Ehlis, A.C., Jacob, C.P. & Fallgatter, A.J. Cortical excitability in adult patients with attention-deficit/hyperactivity disorder (ADHD). Neurosci. Lett. 419, 137–141 (2007).

    Article  CAS  Google Scholar 

  58. Pouget, P., Wattiez, N., Rivaud-Pechoux, S. & Gaymard, B. A fragile balance: perturbation of GABA mediated circuit in prefrontal cortex generates high intraindividual performance variability. PLoS ONE 4, e5208 (2009).

    Article  Google Scholar 

  59. Kaufman, J. et al. Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and Lifetime Version (K-SADS-PL): initial reliability and validity data. J. Am. Acad. Child Adolesc. Psychiatry 36, 980–988 (1997).

    Article  CAS  Google Scholar 

  60. Kim, Y.S. et al. The reliability and validity of Kiddie-Schedule for Affective Disorders and Schizophrenia—Present and Lifetime Version—Korean version (K-SADS-PL-K). Yonsei Med. J. 45, 81–89 (2004).

    Article  Google Scholar 

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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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  1. Hyejung Won and Won Mah: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea

    Hyejung Won, Won Mah, Eunjin Kim, Eun-Kyoung Hahm, Myoung-Hwan Kim, Jeongjin Kim, Daesoo Kim, Changwon Kang & Eunjoon Kim

  2. National Creative Research Initiative Center for Synaptogenesis, KAIST, Daejeon, Korea

    Hyejung Won, Won Mah, Eun-Kyoung Hahm, Myoung-Hwan Kim & Eunjoon Kim

  3. Department of Child and Adolescent Psychiatry, College of Medicine, Seoul National University Hospital, Seoul, Korea

    Jae-Won Kim, Soo-Churl Cho, Boong-Nyun Kim & Min-Sup Shin

  4. Department of Physiology, Seoul National University School of Dentistry, Seoul, Korea

    Sukhee Cho, Jinsoo Seo & Se-Young Choi

  5. Department of Bio and Brain Engineering, KAIST, Daejeon, Korea

    Hyeran Jang & Jaeseung Jeong

  6. Graduate School of Nanoscience and Technology (World Class University), KAIST, Daejeon, Korea

    Eunjoon Kim

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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.

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Correspondence to Changwon Kang or Eunjoon Kim.

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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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