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Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia

Molecular Psychiatry volume 12, pages 1026–1032 (2007)Cite this article

Abstract

Pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1: adenylate cyclase-activating polypeptide 1), a neuropeptide with neurotransmission modulating activity, is a promising schizophrenia candidate gene. Here, we provide evidence that genetic variants of the genes encoding PACAP and its receptor, PAC1, are associated with schizophrenia. We studied the effects of the associated polymorphism in the PACAP gene on neurobiological traits related to risk for schizophrenia. This allele of the PACAP gene, which is overrepresented in schizophrenia patients, was associated with reduced hippocampal volume and poorer memory performance. Abnormal behaviors in PACAP knockout mice, including elevated locomotor activity and deficits in prepulse inhibition of the startle response, were reversed by treatment with an atypical antipsychotic, risperidone. These convergent data suggest that alterations in PACAP signaling might contribute to the pathogenesis of schizophrenia.

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Acknowledgements

We thank Ms Tomoko Shizuno, Keiko Okada and Akiko Murakami for technical assistance and staff of the National Center of Neurology and Psychiatry for recruiting patients and healthy subjects. This work was supported in part by Grants-in-Aid from the Japanese Ministry of Health, Labor and Welfare (H18-kokoro-005, H17-kokoro-001, H17-kokoro-007 and H16-kokoro-002); the Japanese Ministry of Education, Culture, Sports, Science and Technology; Japan Society for the Promotion of Science; CREST (Core Research for Evolutional Science and Technology) of JST (Japan Science and Technology Agency); Japan Foundation for Neuroscience and Mental Health; the Sankyo Foundation of Life Science; and Taisho Pharmaceutical Co Ltd.

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Author notes

  1. R Hashimoto, H Hashimoto and N Shintani: These authors contributed equally to this work.

Authors and Affiliations

  1. The Osaka-Hamamatsu Joint Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    R Hashimoto & H Hashimoto

  2. Department of Psychiatry, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

    R Hashimoto & S Chiba

  3. Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

    R Hashimoto, S Chiba, S Hattori, T Okada, T Mori, T Ohnishi, H Noguchi, H Hori & H Kunugi

  4. Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan

    H Hashimoto, N Shintani, M Nakajima, K Tanaka, N Kawagishi & A Baba

  5. Department of Radiology, National Center Hospital of Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

    K Nemoto, T Mori & T Ohnishi

  6. Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

    T Suzuki & N Iwata

  7. Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan

    N Ozaki

  8. Department of Psychiatry, National Center Hospital of Mental, Nervous, and Muscular Disorders, National Center of Neurology and Psychiatry, Kodaira, Tokyo, Japan

    T Nakabayashi & O Saitoh

  9. Department of Psychiatry, Showa University School of Medicine, Shinagawaku, Tokyo, Japan

    A Kosuga, M Tatsumi & K Kamijima

  10. Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    D R Weinberger

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  1. R Hashimoto
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  16. N Iwata
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  20. A Kosuga
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  21. M Tatsumi
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  22. K Kamijima
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  23. D R Weinberger
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  24. H Kunugi
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Corresponding author

Correspondence to R Hashimoto.

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

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Hashimoto, R., Hashimoto, H., Shintani, N. et al. Pituitary adenylate cyclase-activating polypeptide is associated with schizophrenia. Mol Psychiatry 12, 1026–1032 (2007). https://doi.org/10.1038/sj.mp.4001982

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