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Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice

Nature Neuroscience volume 8, pages 15861594 (2005) | Download Citation

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Abstract

Microdeletions of 22q11.2 represent one of the highest known genetic risk factors for schizophrenia. It is likely that more than one gene contributes to the marked risk associated with this locus. Two of the candidate risk genes encode the enzymes proline dehydrogenase (PRODH) and catechol-O-methyltransferase (COMT), which modulate the levels of a putative neuromodulator (L-proline) and the neurotransmitter dopamine, respectively. Mice that model the state of PRODH deficiency observed in humans with schizophrenia show increased neurotransmitter release at glutamatergic synapses as well as deficits in associative learning and response to psychomimetic drugs. Transcriptional profiling and pharmacological manipulations identified a transcriptional and behavioral interaction between the Prodh and Comt genes that is likely to represent a homeostatic response to enhanced dopaminergic signaling in the frontal cortex. This interaction modulates a number of schizophrenia-related phenotypes, providing a framework for understanding the high disease risk associated with this locus, the expression of the phenotype, or both.

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References

  1. 1.

    et al. Schizophrenia susceptibility associated with interstitial deletions of chromosome 22q11. Proc. Natl. Acad. Sci. USA 92, 7612–7616 (1995).

  2. 2.

    et al. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc. Natl. Acad. Sci. USA 99, 3717–3722 (2002).

  3. 3.

    et al. Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proc. Natl. Acad. Sci. USA 99, 16859–16864 (2002).

  4. 4.

    et al. PRODH mutations and hyperprolinemia in a subset of schizophrenic patients. Hum. Mol. Genet. 11, 2243–2249 (2002).

  5. 5.

    et al. Evidence for association between novel polymorphisms in the PRODH gene and schizophrenia in a Chinese population. Am. J. Med. Genet. B Neuropsychiatr. Genet. 129, 13–15 (2004).

  6. 6.

    et al. Functional consequences of PRODH missense mutations. Am. J. Hum. Genet. 76, 409–420 (2005).

  7. 7.

    et al. Hyperprolinemia is a risk factor for schizoaffective disorder. Mol. Psychiatry 10, 479–485 (2005).

  8. 8.

    et al. Evidence that the gene encoding ZDHHC8 contributes to the risk of schizophrenia. Nat. Genet. 36, 725–731 (2004).

  9. 9.

    et al. A highly significant association between a COMT haplotype and schizophrenia. Am. J. Hum. Genet. 71, 1296–1302 (2002).

  10. 10.

    et al. Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc. Natl. Acad. Sci. USA 98, 6917–6922 (2001).

  11. 11.

    et al. The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nat. Genet. 21, 434–439 (1999).

  12. 12.

    et al. The mammalian brain high-affinity L-proline transporter is enriched preferentially in synaptic vesicles in a subpopulation of excitatory nerve terminals in rat forebrain. J. Neurosci. 19, 21–33 (1999).

  13. 13.

    , , & L-proline activates glutamate and glycine receptors in cultured rat dorsal horn neurons. Mol. Pharmacol. 41, 793–801 (1992).

  14. 14.

    & Proline-induced potentiation of glutamate transmission. Brain Res. 761, 271–282 (1997).

  15. 15.

    et al. Presynaptic BDNF required for a presynaptic but not postsynaptic component of LTP at hippocampal CA3-CA1 synapses. Neuron 39, 975–990 (2003).

  16. 16.

    & Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats. Science 281, 1349–1352 (1998).

  17. 17.

    , , , & Subchronic continuous phencyclidine administration potentiates D-amphetamine-induced frontal cortex dopamine release. Neuropsychopharmacology 28, 34–44 (2003).

  18. 18.

    , , , & Gene expression profiling following chronic NMDA receptor blockade-induced learning deficits in rats. Synapse 50, 171–180 (2003).

  19. 19.

    , , , & Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacology 17, 92–99 (1997).

  20. 20.

    & Effects of repeated treatment with amphetamine or phencyclidine on working memory in the rat. Behav. Brain Res. 134, 267–274 (2002).

  21. 21.

    & Chronic neonatal N-methyl-D-aspartate receptor blockade induces learning deficits and transient hypoactivity in young rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 787–794 (2003).

  22. 22.

    , , , & Longitudinal assessment of methylphenidate effects on oral word production and symptoms in first-episode schizophrenia at acute and stabilized phases. Biol. Psychiatry 45, 680–686 (1999).

  23. 23.

    & Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

  24. 24.

    The neurobiological basis of spontaneous alternation. Neurosci. Biobehav. Rev. 26, 91–104 (2002).

  25. 25.

    et al. The genetic architecture of odor-guided behavior in Drosophila: epistasis and the transcriptome. Nat. Genet. 35, 180–184 (2003).

  26. 26.

    , , & A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193 (2003).

  27. 27.

    et al. Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003).

  28. 28.

    , & Exploring gene expression data with class scores. Pac. Symp. Biocomput. 474–485 (2002).

  29. 29.

    et al. Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116, 127–137 (2003).

  30. 30.

    et al. A comprehensive analysis of 22q11 gene expression in the developing and adult brain. Proc. Natl. Acad. Sci. USA 100, 14433–14438 (2003).

  31. 31.

    & Sodium-dependent proline and glutamate uptake by hippocampal synaptosomes during postnatal development. Brain Res. Dev. Brain Res. 100, 230–233 (1997).

  32. 32.

    , & Beyond the dopamine receptor: The DARPP-32/protein phosphatase-1 cascade. Neuron 23, 435–447 (1999).

  33. 33.

    , , , & Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia. Nat. Genet. 36, 131–137 (2004).

  34. 34.

    et al. Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade. Proc. Natl. Acad. Sci. USA 101, 5099–5104 (2004).

  35. 35.

    & Differential regulation, by MK801, of dopamine receptor gene expression in rat nigrostriatal and mesocorticolimbic systems. Brain Res. 708, 38–44 (1996).

  36. 36.

    , & General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase. Gen. Pharmacol. 25, 813–824 (1994).

  37. 37.

    et al. Neurobiological basis of relapse prediction in stimulant-induced psychosis and schizophrenia: the role of sensitization. Mol. Psychiatry 4, 512–523 (1999).

  38. 38.

    The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res. Brain Res. Rev. 31, 371–384 (2000).

  39. 39.

    , & Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology (Berl.) 174, 111–125 (2004).

  40. 40.

    , , & Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl.) 156, 117–154 (2001).

  41. 41.

    , , & Opposed behavioural outputs of increased dopamine transmission in prefrontocortical and subcortical areas: a role for the cortical D-1 dopamine receptor. Eur. J. Neurosci. 3, 1001–1007 (1991).

  42. 42.

    et al. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc. Natl. Acad. Sci. USA 100, 8993–8998 (2003).

  43. 43.

    Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1, 133–152 (1987).

  44. 44.

    & Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. Ser. B 57, 289–300 (1995).

  45. 45.

    & The Mouse Brain in Stereotaxic Coordinates (Academic Press, New York, 1997).

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Acknowledgements

The authors acknowledge C. Frazier and M. Sribour for technical support and assistance with the mouse colony, J. Chan for help with the behavioral analysis, M. Fazzini for help with the immunocytochemistry and the Sloan-Kettering Genomics Core Laboratory (A. Viale, Director) for help with expression profiling. This research was supported in part by the US National Institutes of Health (grant MH67068 to M.K. and J.A.G. and grant DA07418 to D.S.) and by the New York Academy of Sciences (J.A.G.). J.A.G. is also an EJLB Scholar, a Vicente Young Investigator of the National Alliance for Research on Schizophrenia and Depression (NARSAD) and the recipient of a McKnight Brain Disorders Award. S.S.Z. is a recipient of the NARSAD Young Investigator award and the Hereditary Disease Foundation postdoctoral fellowship. M.P. is supported in part by Telethon, Italy (fellowship no. GFP02011).

Author information

Author notes

    • Stanislav S Zakharenko

    Present address: Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale Street, Memphis, Tennessee 38105, USA.

Affiliations

  1. Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, New York 10032, USA.

    • Marta Paterlini
    • , Wen-Sung Lai
    • , Jun Mukai
    •  & Joseph A Gogos
  2. Human Neurogenetics Laboratory, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.

    • Marta Paterlini
    • , Wen-Sung Lai
    •  & Maria Karayiorgou
  3. Center for Neurobiology and Behavior, Columbia University, 722 West 168th Street, New York, New York 10032, USA.

    • Stanislav S Zakharenko
    • , Steven A Siegelbaum
    •  & Joseph A Gogos
  4. Genome Center and Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, 1150 St. Nicholas Avenue, New York, New York 10032, USA.

    • Jie Qin
    •  & Paul Pavlidis
  5. Departments of Neurology and Psychiatry, Columbia University College of Physicians and Surgeons, 701 West 168th Street, New York, New York 10032, USA.

    • Hui Zhang
    •  & David Sulzer
  6. Department of Pharmacology, University of Utrecht, Sorbonnelaan 16, 3584 CA Utrecht, The Netherlands.

    • Koen G C Westphal
    •  & Berend Olivier
  7. Howard Hughes Medical Institute, Columbia University, 722 West 168th Street, New York, New York 10032, USA.

    • Steven A Siegelbaum
  8. Department of Pharmacology, Columbia University, 722 West 168th Street, New York, New York 10032, USA.

    • Steven A Siegelbaum

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Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Maria Karayiorgou or Joseph A Gogos.

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DOI

https://doi.org/10.1038/nn1562

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