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Volume 17, Number 19,
Issue of October 1, 1997
pp. 7288-7296
Copyright ©1997 Society for Neuroscience
Disruption of a Single Allele of the Nerve Growth Factor Gene
Results in Atrophy of Basal Forebrain Cholinergic Neurons and Memory
Deficits
Karen S. Chen1,
Merry
C. Nishimura1,
Mark P. Armanini1,
Craig Crowley2,
Susan D. Spencer3, and
Heidi S. Phillips1
Departments of 1 Neuroscience, 2 Molecular
Biology, and 3 Molecular Oncology, Genentech, Inc., South
San Francisco, California 94080
Administration of nerve growth factor (NGF) to aged or lesioned
animals has been shown to reverse the atrophy of basal forebrain cholinergic neurons and ameliorate behavioral deficits. To examine the
importance of endogenous NGF in the survival of basal forebrain cholinergic cells and in spatial memory, mice bearing a disruption mutation in one allele of the NGF gene were studied. Heterozygous mutant mice (ngf+/ ) have reduced levels of NGF mRNA
and protein within the hippocampus and were found to display
significant deficits in memory acquisition and retention in the Morris
water maze. The behavioral deficits observed in NGF-deficient mice were
accompanied by both shrinkage and loss of septal cells expressing
cholinergic markers and by a decrease in cholinergic innervation of the
hippocampus. Infusions of NGF into the lateral ventricle of adult
ngf+/ mice abolished the deficits on the water maze
task. Prolonged exposure to NGF may be required to induce cognitive
effects, because reversal of the acquisition deficit was seen after
long (5 weeks) but not short (3 d) infusion. Although NGF
administration did not result in any improvement in the number of
septal cells labeled for choline acetyltransferase, this treatment did
effectively correct the deficits in both size of cholinergic neurons
and density of cholinergic innervation of the hippocampus. These
findings demonstrate the importance of endogenous NGF for survival and
function of basal forebrain cholinergic neurons and reveal that partial
depletion of this trophic factor is associated with measurable deficits in learning and memory.
Key words:
NGF;
neurotrophin;
cholinergic;
learning;
memory;
cell
death;
gene deletion
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