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

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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Figure 1: Electrophysiological characterization of Prodh-deficient mice.
Figure 2: Behavioral characterization of Prodh-deficient mice.
Figure 3: RNA expression profiling in the frontal cortex of Prodh-deficient mice.
Figure 4: Validation of RNA expression profiling of Comt in Prodh-deficient mice.
Figure 5: Dopaminergic dysregulation in the frontal cortex of Prodh-deficient mice.
Figure 6: Dopamine-related signaling molecules in the frontal cortex of Prodh-deficient mice.
Figure 7: Epistatic interaction between Prodh and Comt at the behavioral level.

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References

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Liu, H. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  5. Li, T. 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).

    Article  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Egan, M.F. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Renick, S.E. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Henzi, V., Reichling, D.B., Helm, S.W. & MacDermott, A.B. L-proline activates glutamate and glycine receptors in cultured rat dorsal horn neurons. Mol. Pharmacol. 41, 793–801 (1992).

    CAS  PubMed  Google Scholar 

  14. Cohen, S.M. & Nadler, J.V. Proline-induced potentiation of glutamate transmission. Brain Res. 761, 271–282 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  17. Balla, A., Sershen, H., Serra, M., Koneru, R. & Javitt, D.C. Subchronic continuous phencyclidine administration potentiates D-amphetamine-induced frontal cortex dopamine release. Neuropsychopharmacology 28, 34–44 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. O'Donnell, J., Stemmelin, J., Nitta, A., Brouillette, J. & Quirion, R. Gene expression profiling following chronic NMDA receptor blockade-induced learning deficits in rats. Synapse 50, 171–180 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Jentsch, J.D., Tran, A., Le, D., Youngren, K.D. & Roth, R.H. Subchronic phencyclidine administration reduces mesoprefrontal dopamine utilization and impairs prefrontal cortical-dependent cognition in the rat. Neuropsychopharmacology 17, 92–99 (1997).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  21. Latysheva, N.V. & Rayevsky, K.S. 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).

    Article  CAS  PubMed  Google Scholar 

  22. Szeszko, P.R., Bilder, R.M., Dunlop, J.A., Walder, D.J. & Lieberman, J.A. 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).

    Article  CAS  PubMed  Google Scholar 

  23. Phillips, R.G. & LeDoux, J.E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav. Neurosci. 106, 274–285 (1992).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Bolstad, B.M., Irizarry, R.A., Astrand, M. & Speed, T.P. A comparison of normalization methods for high density oligonucleotide array data based on variance and bias. Bioinformatics 19, 185–193 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Pavlidis, P., Lewis, D.P. & Noble, W.S. Exploring gene expression data with class scores. Pac. Symp. Biocomput. 474–485 (2002).

  29. Matsumoto, M. 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).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Cohen, S.M. & Nadler, J.V. Sodium-dependent proline and glutamate uptake by hippocampal synaptosomes during postnatal development. Brain Res. Dev. Brain Res. 100, 230–233 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Greengard, P., Allen, P.B. & Nairn, A.C. Beyond the dopamine receptor: The DARPP-32/protein phosphatase-1 cascade. Neuron 23, 435–447 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Emamian, E.S., Hall, D., Birnbaum, M.J., Karayiorgou, M. & Gogos, J.A. Convergent evidence for impaired AKT1-GSK3β signaling in schizophrenia. Nat. Genet. 36, 131–137 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Beaulieu, J.M. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Healy, D.J. & Meador-Woodruff, J.H. Differential regulation, by MK801, of dopamine receptor gene expression in rat nigrostriatal and mesocorticolimbic systems. Brain Res. 708, 38–44 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Kaakkola, S., Gordin, A. & Männistö, P.T. General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase. Gen. Pharmacol. 25, 813–824 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  38. Laruelle, M. 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).

    Article  CAS  PubMed  Google Scholar 

  39. Castner, S.A., Goldman-Rakic, P.S. & Williams, G.V. Animal models of working memory: insights for targeting cognitive dysfunction in schizophrenia. Psychopharmacology (Berl.) 174, 111–125 (2004).

    Article  CAS  Google Scholar 

  40. Geyer, M.A., Krebs-Thomson, K., Braff, D.L. & Swerdlow, N.R. Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review. Psychopharmacology (Berl.) 156, 117–154 (2001).

    Article  CAS  Google Scholar 

  41. Vezina, P., Blanc, G., Glowinski, J. & Tassin, J.P. 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).

    Article  PubMed  Google Scholar 

  42. Gerber, D.J. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

  45. Franklin, K.B.J. & Paxinos, G. The Mouse Brain in Stereotaxic Coordinates (Academic Press, New York, 1997).

    Google Scholar 

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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).

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Correspondence to Maria Karayiorgou or Joseph A Gogos.

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Paterlini, M., Zakharenko, S., Lai, WS. et al. Transcriptional and behavioral interaction between 22q11.2 orthologs modulates schizophrenia-related phenotypes in mice. Nat Neurosci 8, 1586–1594 (2005). https://doi.org/10.1038/nn1562

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