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The Journal of Neuroscience, July 1, 2001, 21(13):4625-4636

Pituitary Adenylyl Cyclase-Activating Peptides and -Amidation in Olfactory Neurogenesis and Neuronal Survival In Vitro

Donna E. Hansel¹, Victor May⁴, Betty A. Eipper³, and Gabriele V. Ronnett^{1, 2}

Departments of ¹ Neuroscience and ² Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, ³ Department of Neuroscience, University of Connecticut Health Center, Farmington, Connecticut 06030, and ⁴ Department of Anatomy and Neurobiology, The University of Vermont College of Medicine, Burlington, Vermont 05405

We investigated the role of amidated neuropeptides, and specifically pituitary adenylyl cyclase-activating polypeptide (PACAP), in olfactory neurogenesis and olfactory receptor neuronal survival. Using both immunohistochemistry and in situ hybridization, we find that both peptidylglycine -amidating monooxygenase (PAM), the enzyme responsible for amidation and therefore activation of all amidated neuropeptides, and amidated PACAP are expressed in developing and adult olfactory epithelium. Amidated PACAP is highly expressed in proliferative basal cells and in immature olfactory neurons. The PACAP-specific receptor PAC₁ receptor is also expressed in this population, establishing that these cells can be PACAP responsive. Experiments were conducted to determine whether amidated neuropeptides, such as PACAP38, might function in olfactory neurogenesis and neuronal survival. Addition of PACAP38 to olfactory cultures increased the number of neurons to >250% of control and stimulated neuronal proliferation and survival. In primary olfactory cultures, pharmacologically decreased PAM activity, as well as neutralization of PACAP38, caused neuron-specific loss that was reversed by PACAP38. Mottled (Brindled) mice, which lack a functional ATP7A copper transporter and serve as a model for Menkes disease, provided an in vivo partial loss-of-function PAM knock-out. These mice had decreased amidated PACAP production and concomitant decreased numbers of olfactory receptor neurons. These data establish amidated peptides and specifically PACAP as having important roles in proliferation in the olfactory system and suggest that a similar function exists in vivo.

Key words: PAM; PACAP38; olfaction; neurogenesis; Mottled (Brindled) mice; Menkes disease

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21134625-12$05.00/0

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