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Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype

Molecular Psychiatry volume 11, pages 787–793 (2006)Cite this article

Abstract

Selectively bred apomorphine susceptible (APO-SUS) rats display a complex behavioral phenotype remarkably similar to that of human neurodevelopmental disorders, such as schizophrenia. We recently found that the APO-SUS rats have only one or two Aph-1b gene copies (I/I and II/II rats, respectively), whereas their phenotypic counterpart has three copies (III/III). Aph-1b is a component of the γ-secretase enzyme complex that is involved in multiple (neuro)developmental signaling pathways. Nevertheless, surprisingly little is known about γ-secretase expression during development. Here, we performed a longitudinal quantitative PCR study in embryos and the hippocampus of I/I, II/II and III/III rats, and found gene-dosage dependent differences in Aph-1b, but not Aph-1a, mRNA expression throughout pre- and post-natal development. On the basis of the developmental mRNA profiles, we assigned relative activities to the various Aph-1a and -1b gene promoters. Furthermore, in the three rat lines, we observed both tissue-specific and temporal alterations in γ-secretase cleavage activity towards one of its best-known substrates, the amyloid-β precursor protein APP. We conclude that the low levels of Aph-1b mRNA and γ-secretase activity observed in the I/I and II/II rats during the entire developmental period may well underlie their complex phenotype.

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Acknowledgements

This work was funded by grants from the Netherlands Organization for Scientific Research (NWO). We thank Luuk Lubbers for animal breeding, Nick van Bakel for technical assistance and Liselotte van der Kam for statistical support.

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Authors and Affiliations

  1. Department of Molecular Animal Physiology, Nijmegen Center for Molecular Life Sciences (NCMLS), Radboud University, Nijmegen, The Netherlands

    M W Coolen, K M J van Loo & G J M Martens

  2. Department of Psychoneuropharmacology, Radboud University, Nijmegen, The Netherlands

    B A Ellenbroek & A R Cools

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  1. M W Coolen
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  2. K M J van Loo
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  3. B A Ellenbroek
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  4. A R Cools
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Correspondence to G J M Martens.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Coolen, M., van Loo, K., Ellenbroek, B. et al. Ontogenic reduction of Aph-1b mRNA and γ-secretase activity in rats with a complex neurodevelopmental phenotype. Mol Psychiatry 11, 787–793 (2006). https://doi.org/10.1038/sj.mp.4001846

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