T. Hökfelta,*, C. Brobergera, X.
Zhanga,b, M. Dieza, J.
Koppa, Z.-Q. Xua, M. Landrya,
L. Baoc, M. Schallingd, J. Koistinahoa,e., S. J. DeArmondf,g, S. Prusinerg,h, J. Gongb, J. H. Walshi
aDepartment of Neuroscience, Karolinska Institute, S-171 77 Stockholm, Sweden, bDepartment of Neurobiology, 17 Chang Le Xi Road, Xi'an 710032, People's Republic of China, cDepartment of Aerospace, 17 Chang Le Xi Road, Xi'an 710032, People's Republic of China, dDepartment of Molecular Medicine, Karolinska Hospital, S-171 76 Stockholm, Sweden, eA.I, Virtanen Institute, University of Kuopio, Kuopio, Finland, fDepartment of Pathology, University of California, San Francisco, CA, USA, gDepartment of Neurology, University of California, San Francisco, CA, USA, hDepartment of Biochemistry and Biophysics, University of California, San Francisco, CA, USA, iGastroenteric Biology Center (CURE), Los Angeles, CA, USA
Using immunohistochemical and in situ hybridization methodologies the localization of neuropeptide tyrosine (NPY) and two of its receptors, the Y1- and the Y2-receptor (R), has been analysed in various tissues in normal animals and animals subjected to different experimental procedures as well as animals with a genetic and an acquired disease. (1) Dorsal root ganglion (DRG) neurons are discussed with special focus on the effect of peripheral nerve injury. In normal DRG neurons NPY cannot be detected, whereas Y1-R mRNA and Y1-R-like immunoreactivity (LI) are strongly expressed. The Y1-Rs decorate the membrane of the cell soma and are not transported peripherally into the axonal branches. Y2-R mRNA levels are low. After axotomy there is a marked increase in NPY, a decrease in Y1-Rs and an increase in Y2-Rs. The Y2-R is transported centrifugally. These findings suggest that NPY-ergic mechanisms participate in the adaptive changes of sensory neurons in response to injury. (2) Using specific antibodies the cellular and subcellular localization of the Y1-R protein have been analysed in cerebral blood vessels. The results demonstrate high concentrations of receptors in smooth muscle cells around pial arterioles with lower numbers in large vessels on the basal surface of the brain. In many regions the receptors 'disappear' after the aterioles have entered the brain tissue. At the ultrastructural level the receptors are found both on the endothelial and peripheral side of the muscle cells as well as laterally, where muscle cells oppose each other. The receptor protein is often associated with small vesicles. No NPY-positive nerve fibers were found around the Y1-R-rich arterioles, but they were only seen around the arteries with low Y1-R levels. The Y1-R-rich arterioles were, however, seen close to numerous NPY-positive fibers originating from central interneurons. These findings raise the possibility that centrally originating NPY can influence cerebral blood flow, possibly by stimulating NPY-Rs on the peripheral side of the muscle cells. However, also blood borne NPY, released under special conditions, such as stress from sympathetic nerves and the adrenal medulla and transported with blood, may stimulate receptors on the endothelial side of the smooth muscle cells. (3) In the arcuate nucleus Y1- and Y2-Rs are found, whereby the Y1-Rs are located in its ventro-medial portion and co-localized with POMC peptides, and the Y2-R in its ventromedial part, partly co-localized with NPY. NPY nerve endings make synaptic contact with the POMC/Y1-R-positive neurons. In a mouse model for genetic anorexia very high levels of NPY were observed in arcuate neurons as compared to control mice. However, NPY mRNA levels were not different between the two groups. Taken together these findings are in good agreement with the view that NPY in the arcuate nucleus plays an important role in regulating feeding behaviour. (4) After intracerebral prion inoculation in mice an upregulation of NPY mRNA levels was observed in CA3 pyramidal neurons, and this effect was seen at a time point just before the first behavioural symptoms were manifested. At approximately the same time there was a dramatic decrease in Y2-R binding in strata oriens and radiatum of the CA1 region of the hippocampus, whereas in other regions no changes or much smaller changes were observed. Also, there was only a very slight decrease in Y2-R mRNA levels in CA3 neurons. It thus appears as if the prion disease prevents ligand binding to the Y2-R, perhaps by influencing traffic of receptor proteins, possibly at the level of cell membrane-associated caveolae, which have been implicated in the conversion of normal protein to scrapie protein. It is possible that these changes in NPY-ergic mechanisms may underlie some of the central symptoms associated with the prion disease. Taken together these findings underline the plasticity in expression of peptides and peptide receptors in response to various stimuli; they support roles for peptides in situations where the organism is challenged, reguiring expression of molecules of importance for survival and regeneration and, in general terms, for counteracting and correcting adverse effects.
*Corresponding author: Tomas.Hokfelt@neuro.ki.se
Brain Research Reviews 26 (1998)
Copyright © 1998 Elsevier Science B. V. All rights reserved.