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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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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DOI: https://doi.org/10.1038/sj.mp.4001982
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