T. Hökfelt a,*, C. Broberger a, X.
Zhang a,b, M. Diez a, J.
Koppa, Z.-Q. Xu a, M. Landry a,
L. Bao c, M. Schalling d, J. Koistinaho
a,e., S. J. DeArmond f,g, S. Prusiner
g,h, J. Gong b, J. H. Walsh
i
aDepartment of Neuroscience, Karolinska Institute,
S-171 77 Stockholm, Sweden, b Department 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,
d Department of Molecular Medicine, Karolinska
Hospital, S-171 76 Stockholm, Sweden, eA.I, Virtanen
Institute, University of Kuopio, Kuopio, Finland, f
Department of Pathology, University of California, San Francisco,
CA, USA, g Department of Neurology, University of
California, San Francisco, CA, USA, h Department of
Biochemistry and Biophysics, University of California, San
Francisco, CA, USA, i Gastroenteric Biology Center
(CURE), Los Angeles, CA, USA
Abstract
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)
154-166
Copyright © 1998 Elsevier Science B. V. All rights
reserved.
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