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Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Is Involved in Adult Mouse Hippocampal Neurogenesis After Stroke

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Abstract

In the subgranular zone (SGZ) of the hippocampus, neurogenesis persists throughout life and is upregulated following ischemia. Accumulating evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to recovery after stroke. However, the mechanisms underlying the upregulation of neurogenesis are unclear. We have demonstrated that a neuropeptide, pituitary adenylate cyclase-activating polypeptide (PACAP), exerts a wide range of effects on neural stem cells (NSCs) during neural development. Here, we examined the effects of endogenous and exogenous PACAP in adult NSCs of the SGZ. Immunostaining showed expression of the PACAP receptor PAC1R in nestin-positive NSCs of adult naive mice. PACAP injection into the lateral ventricle increased bromodeoxyuridine (BrdU)-positive proliferative cells in the SGZ. These data suggest that PACAP promoted the proliferation of NSCs. In global ischemia model mice, the number of BrdU-positive cells was increased in wild-type mice but not in PACAP heterozygous knockout mice. The BrdU-positive cells that increased in number after ischemia were immunopositive for SOX2, a marker of NSCs, and differentiated into NeuN-positive mature neurons at 4 weeks after ischemia. These findings suggest that PACAP contributes to the proliferation of NSCs and may be associated with recovery after brain injury.

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Acknowledgments

This study was supported in part by JSPS KAKENHI Grants (23249079, 24592681, 25861289, 26293020, 26670122, 15K15670, and 15H01288) and the JSPS Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers, Grant No. S2603 (HH).

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Authors and Affiliations

  1. Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan

    Minako Matsumoto, Koichi Sugiyama, Shun Sasaki & Akira Miyazaki

  2. Laboratory of Regulatory Biology, Graduate School of Science and Engineering, University of Toyama, Toyama, Japan

    Tomoya Nakamachi

  3. Center for Biotechnology, Showa University, Tokyo, Japan

    Jun Watanabe

  4. Department of Anatomy, Showa University School of Medicine, Tokyo, Japan

    Hirokazu Ohtaki, Norimitsu Murai, Zhifang Xu & Tamotsu Seki

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

    Hitoshi Hashimoto

  6. iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

    Hitoshi Hashimoto

  7. Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka, Japan

    Hitoshi Hashimoto

  8. Department of Neuropeptide Drug Discovery, Hoshi University School of Pharmacy and Pharmaceutical Sciences, 2-4-41 Ebara, Shinagawa-ku, Tokyo, 142-8051, Japan

    Seiji Shioda

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  1. Minako Matsumoto
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  2. Tomoya Nakamachi
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  3. Jun Watanabe
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  4. Koichi Sugiyama
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  5. Hirokazu Ohtaki
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  6. Norimitsu Murai
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  7. Shun Sasaki
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  8. Zhifang Xu
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  9. Hitoshi Hashimoto
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  10. Tamotsu Seki
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  11. Akira Miyazaki
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  12. Seiji Shioda
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Corresponding author

Correspondence to Seiji Shioda.

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Animal care and all experimental procedures involving animal use were approved by the Institutional Animal Care and Use Committee of Showa University.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Schematic experimental schedule for BrdU labeling. (GIF 14 kb)

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Matsumoto, M., Nakamachi, T., Watanabe, J. et al. Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Is Involved in Adult Mouse Hippocampal Neurogenesis After Stroke. J Mol Neurosci 59, 270–279 (2016). https://doi.org/10.1007/s12031-016-0731-x

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  • DOI: https://doi.org/10.1007/s12031-016-0731-x

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