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Journal of Neuroscience, Vol 8, 2986-2999, Copyright © 1988 by Society for Neuroscience
Rescue of lesioned septal cholinergic neurons by nerve growth factor: specificity and requirement for chronic treatment
CN Montero and F Hefti
Department of Neurology, University of Miami Medical School, Florida 33101.
We earlier reported that chronic intraventricular injections of NGF into
adult rats with partial transection of the fimbria prevent the
lesion-induced disappearance of cholinergic neurons in the medial septal
nucleus and the diagonal band of Broca (Hefti, 1986). The present study
assessed the specificity and treatment requirements of this effect of NGF.
Immunohistochemical visualization of NGF receptors (NGF-R) revealed that
these molecules are selectively located in forebrain cholinergic neurons of
unlesioned brains. Fimbrial transection resulted in transient accumulation
of NGF-R in proximal stumps of lesioned axons but failed to induce the
expression of NGF-R by other cells in the septal area or near the lesion.
Two to three weeks after lesioning, the number of septal neurons expressing
NGF-R was reduced by approximately 50% in parallel with the reduction of
the number of neurons expressing cholinergic marker enzymes. Repeated
intraventricular NGF injections during 4 weeks prevented the disappearance
of these cells. Fimbrial transections also reduced the number of septal
GABAergic neurons visualized by glutamate decarboxylase
immunohistochemistry. The loss of GABAergic neurons was not prevented by
NGF. These findings suggest that NGF prevents the lesion-induced
degeneration of cholinergic neurons by directly acting on NGF-R expressed
by cholinergic cells and that NGF does not affect any neuron with an axonal
lesion. Delayed start of the NGF treatment failed to prevent the
disappearance of lesioned cholinergic neurons, providing evidence that NGF
treatment indeed promotes the survival of these cells rather than simply
upregulating the expression of transmitter-specific enzymes. A single
injection of NGF at the time of the lesion was not sufficient to prevent
the lesion-induced degeneration of cholinergic neurons. Furthermore,
termination of chronic NGF treatment after 4 weeks was followed by loss of
septal cholinergic neurons after an additional 4 weeks. These findings
suggest that the continuous presence of NGF during more than 4 weeks is
required to prevent the degeneration of cholinergic cells. The data are
discussed in the context of a possible physiological role of NGF in the
function of adult forebrain cholinergic neurons.
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