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The gene encoding proline dehydrogenase modulates sensorimotor gating in mice

Nature Genetics volume 21, pages 434–439 (1999)Cite this article

Abstract

Hemizygous cryptic deletions of the q11 band of human chromosome 22 have been associated with a number of psychiatric and behavioural phenotypes, including schizophrenia1,2,3. Here we report the isolation and characterization of PRODH, a human homologue of Drosophila melanogaster sluggish-A (slgA), which encodes proline dehydrogenase responsible for the behavioural phenotype of the slgA mutant4. PRODH is localized at chromosome 22q11 in a region deleted in some psychiatric patients. We also isolated the mouse homologue of slgA (Prodh), identified a mutation in this gene in the Pro/Re hyperprolinaemic mouse strain and found that these mice have a deficit in sensorimotor gating accompanied by regional neurochemical alterations in the brain. Sensorimotor gating is a neural filtering process that allows attention to be focused on a given stimulus, and is affected in patients with neuropsychiatric disorders5. Furthermore, several lines of evidence suggest that proline may serve as a modulator of synaptic transmission in the mammalian brain. Our observations, in conjunction with the chromosomal location of PRODH, suggest a potential involvement of this gene in the 22q11-associated psychiatric and behavioural phenotypes.

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Figure 1: Amino acid sequence, cross-specises comparison and mapping of PRODH .
Figure 2: Expression pattern of human PRODH, mouse and rat orthologues.
Figure 3: Effect of Prodh mutation on proline levels and exploratory behaviours.
Figure 4: Morphological and neurochemical analysis of Prodh–/– brains.
Figure 5: Sensorimotor gating in Prodh-/- mice.

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Acknowledgements

We thank B.L. Galke, Y. Jiao and L. Malinova for technical assistance; C. Baptista and A. Matilla for help in the initial phases of this work; M. Morgan and D. Pfaff for help with setting up the behavioural assays; M. McGee-Harper for help with the statistical analysis; and D. Pfaff for useful comments on the manuscript. Support for this work was provided by a grant from the Patterson Trust and the Irma T. Hirschl Foundation to M.K.

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Author notes

  1. Joseph Gogos and Miklos Santha: These authors contributed equally to this work

Affiliations

  1. The Rockefeller University, New York, 10021, New York, USA

    Joseph Gogos, Miklos Santha, Zoltan Takacs, Louis R Lucas & Maria Karayiorgou

  2. Columbia University, College of Physicians & Surgeons, Center for Neurobiology & Behavior, New York, New York, 10032, USA

    Joseph Gogos

  3. Psychology Department, Hunter College, New York, 10021, New York, USA

    Kevin D Beck & Victoria Luine

  4. Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, 27710, North Carolina, USA

    J. Victor Nadler

Authors
  1. Joseph Gogos
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  2. Miklos Santha
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  5. Victoria Luine
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  6. Louis R Lucas
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  8. Maria Karayiorgou
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Correspondence to Maria Karayiorgou.

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Gogos, J., Santha, M., Takacs, Z. et al. The gene encoding proline dehydrogenase modulates sensorimotor gating in mice. Nat Genet 21, 434–439 (1999). https://doi.org/10.1038/7777

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