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Volume 17, Number 20,
Issue of October 15, 1997
pp. 7644-7654
Copyright ©1997 Society for Neuroscience
A Role for TrkA during Maturation of Striatal and Basal Forebrain
Cholinergic Neurons In Vivo
Received May 8, 1997; revised July 30, 1997; accepted Aug. 5, 1997.
Anne M. Fagan1,
Melinda Garber2,
Mariano Barbacid2,
Inmaculada Silos-Santiago2, and
David M. Holtzman1
1 Departments of Neurology, Molecular Biology, and
Pharmacology, and the Center for the Study of Nervous System Injury,
Washington University School of Medicine, St. Louis, Missouri 63110, and 2 Department of Molecular Oncology, Bristol-Myers
Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543
Nerve growth factor (NGF), acting via the TrkA receptor, has been
shown to regulate the survival and maturation of specific neurons of
the peripheral nervous system. Furthermore, exogenous NGF has potent
actions on TrkA-expressing cholinergic neurons of the basal forebrain
(BFCNs) and striatum. However, initial analysis of mice lacking NGF or
TrkA revealed that forebrain cholinergic neurons were present in these
animals through the fourth postnatal week. Because of the potential
effects of NGF/TrkA interactions on these developing neurons, we have
analyzed quantitatively the striatal and basal forebrain cholinergic
neurons in trkA knock-out mice. By postnatal day (P)
7/8, forebrain cholinergic neurons are smaller in trkA
( /) mice than those in wild-type littermate controls. However,
cholinergic neuron number and fiber density in the hippocampus, a
target region of BFCNs, are grossly intact. Interestingly, by P20-P25
trkA knock-outs contain significantly fewer (20-36%)
and smaller cholinergic neurons in both the striatum and septal
regions, as compared with controls. Cholinergic fiber density within
the hippocampus also is depleted in knock-outs by the end of the second
postnatal week. Contrary to some predictions, despite expression of
p75NTR in the absence of trkA in
BFCNs of these knock-out mice, many cells, although smaller, are still
alive at P25. Our data suggest that, in the absence of NGF/TrkA
signaling, striatal cholinergic neurons and BFCNs do not mature fully
and that BFCNs begin to atrophy and/or die surrounding the time of
target innervation.
Key words:
TrkA;
nerve growth factor;
neurotrophin;
knock-out;
development;
p75NTR
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