Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is a pleiotropic peptide with functions in development and throughout life [4]. PACAP knockout (KO) animals will die shortly after birth due to an inability to maintain core body temperature [5]. Our observation that preventing hypothermia in PACAP KO pups does not eliminate poor survival suggests that other functions such as olfactory mediated feeding may be disturbed. Both PACAP and its G-protein coupled receptor (PAC1) are highly expressed in the olfactory bulb (OB) throughout life suggesting PACAP plays an important role in the development, survival and replacement of neurons within the bulb. Surprisingly, there have been no studies on the role of PACAP in modulating the Ca[2+] activity, migration, and maturation of developing OB neurons. In other CNS regions, Ca[2+] activity in the form of spontaneous oscillations is critical for the establishment and survival of developing neuronal circuitry, especially prior to sensory input [6]. GABA is excitatory in immature neurons and has been implicated in this early developmental activity but the control of maturation in olfactory interneurons is poorly understood. However, our preliminary data show that PACAP induces transient and sustained Ca[2+] oscillations in multiple cell types of the neonatal OB. Our focus in the first aim will be on the developing GABAergic granule cells (GCs) because they are thought to express PAC1Rs and can be identified using GAD2- and Dlx2- tdTomato transgenic mice. The developing GCs will be evaluated for PACAP responses and their maturity tested with GABA, which will be an excitatory neurotransmitter for the immature cells which maintain high intracellular Cl- levels and depolarize with GABA stimulation.
The second aim will be determining the role of PACAP in the migration and maturation of immature OB interneurons. It will be directly accomplished using migration assays on cultured GAD2 or Dlx2 tdTomato mice OB cells. Morphological changes associated with maturation will also be examined. This proposal will examine the role of PACAP during early postnatal development of OB circuitry and is based on studies of PACAP and PAC1 receptor expression in the OB and other brain regions. However, my studies are the first dynamic imaging studies of PACAP in identified cells of neonatal OB. Because little is known about the function of PACAP in the OB, the emphasis of my proposal will be to lay the foundation for future understanding of how PACAP affects the development of OB circuitry. A number of neurological diseases such as autism, bipolar disease, and schizophrenia are thought to originate from problems in early development of neuronal circuits. Understanding the role of PACAP in early circuitry development may provide a novel therapeutic target for these devastating diseases. Furthermore, understanding how PACAP affects developing interneurons may aid in designing strategies for adult neurogenesis following injury or disease.

Public Health Relevance

PACAP is a neuropeptide found at high levels during development and in regions of the CNS that continue to generate new neurons in adulthood such as the dentate gyrus and the olfactory bulb. This is the first study to examine physiological effects of PACAP on developing olfactory bulb neurons. Understanding the role of PACAP in modulating Ca[2+] and migration in developing neurons of olfactory bulb may provide novel avenues for therapeutic use of PACAP during development or following CNS injury or neurodegenerative disease.

National Institute of Health (NIH)
National Institute on Deafness and Other Communication Disorders (NIDCD)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDC1-SRB-L (48))
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Sklare, Dan
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University of Utah
Schools of Medicine
Salt Lake City
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Ying, Guoxin; Avasthi, Prachee; Irwin, Mavis et al. (2014) Centrin 2 is required for mouse olfactory ciliary trafficking and development of ependymal cilia planar polarity. J Neurosci 34:6377-88