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Journal of Neuroscience, Vol 13, 4146-4156, Copyright © 1993 by Society for Neuroscience
Brain-derived neurotrophic factor (BDNF) prevents the degeneration of medial septal cholinergic neurons following fimbria transection
JK Morse, SJ Wiegand, K Anderson, Y You, N Cai, J Carnahan, J Miller, PS DiStefano, CA Altar and RM Lindsay
Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591-6707.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin
family, supports the survival of developing basal forebrain cholinergic
neurons in vitro and is retrogradely transported by cholinergic neurons of
the medial septum and diagonal band following intrahippocampal injections
in vivo. To substantiate a potential role for BDNF in the maintenance of
forebrain cholinergic neurons in the adult brain, we assessed the ability
of BDNF to sustain the phenotype of medial septal cholinergic neurons
following a unilateral transection of the fimbria. BDNF, NGF, or vehicle
solutions were infused continuously in adult female rats either into the
lateral ventricle (intracerebroventricularly) or directly into the septum
for 2 weeks beginning at the time of the transection. In vehicle-infused
animals, only 28% of the ChAT-immunoreactive neurons remained on the side
ipsilateral to the lesion compared to the contralateral intact side. When
infused intracerebroventricularly, both BDNF and NGF reduced the extent of
the phenotypic loss, in that 44% and 68%, respectively, of the
ChAT-immunopositive neurons remained on the lesioned side. Intraseptal
infusion proved even more effective, in that following BDNF and NGF
treatment 60% and 86%, respectively, of the normal complement of
ChAT-immunopositive neurons were apparent on the side ipsilateral to the
lesion. Similar results were obtained when an antibody to the low- affinity
NGF receptor was used to identify the cholinergic neurons. To determine if
the apparent greater efficacy of NGF compared to BDNF might be related to
differences in delivery, we examined the patterns of distribution of
radiolabeled BDNF and NGF injected into the lateral ventricle. 125I-BDNF
showed only very little diffusion from the ventricles into the adjacent
neural tissue and negligible retrograde labeling of the neurons within the
basal forebrain. 125I-NGF, however, diffused readily into the brain,
resulting in widespread retrograde labeling of basal forebrain neurons. A
similarly limited distribution pattern was observed where BDNF was detected
immunohistochemically in animals infused intracerebroventricularly (12
micrograms/d) for 2 weeks. In contrast, when delivered intraseptally, the
same dose of BDNF exhibited a widespread diffusion within the surrounding
neuropil and retrograde labeling of neurons in the medial septum and the
vertical limb of the diagonal band. Thus, when delivered effectively, BDNF
has a substantial capacity to rescue axotomized cholinergic neurons.
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