Brain-derived neurotrophic factor (BDNF) prevents the degeneration of medial septal cholinergic neurons following fimbria transection

Abstract

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.

Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain

“…Free-floating sections were incubated in antiserum directed against 5-HT (Incstar Corp., Stillwater, MN), diluted 1: 15,000 (Mamounas et al, 1991). To assess the intracerebral distribution of the infused BDNE adjacent sections were incubated with a turkey anti-BDNF antibody (Amgen, Inc.) at a dilution of 1:7,500 (Morse et al, 1993). Bound immunoglobulin was visualized with the avidin-biotin-peroxidase method (Vector Laboratories, Burlingame, CA), using diaminobenzidine tetrachloride as the substrate.…”

Brain‐derived neurotrophic factor‐transduced fibroblasts: Production of BDNF and effects of grafting to the adult rat brain

“…NGF, infused intraventricularly, is able to prevent the loss of approximately 90% of the cholinergic neurons. Intraventricular and intraparenchymal infusions of BDNF also rescue septal Morse et al, 1993). We investigated whether FF/BDNF grafts placed directly in the septum could avert cholinergic neuronal degeneration following fimbria-fornix lesions, as do grafts of FF/NGF (Rosenberg et al, 1988).…”

“…Cholinergic neurons are rescued after axotomy following daily infusion of microgram amounts of BDNF Morse et al, 1993). However, the preventive effect of BDNF on degeneration of cholinergic cells after axotomy is significantly more pronounced when the trophic molecule is infused intraparenchymally rather than intraventricularly (Morse et al, 1993), presumably because intraparenchymal infusion circumvents the amount of BDNF that can bind to the truncated trkB receptor present on the ventricular wall. Because of the presence of the truncated form of the trkB receptor in the parenchyma as well, the proximity of the injection site is a crucial determinant.…”

“…A decrease in neurotrophic factors during aging has also been hypothesized to predicate degenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD;Appel, 1981;Hefti, 1983), where the loss of dopaminergic neurons of the substantia nigra pars compacta (SNC) is correlated with the major motor disability of PD, and the loss of cholinergic neurons in the basal forebrain is associated with memory loss in AD (Bernheimer et al, 1973;Olton, 1990). Although the etiology and mechanisms underlying the selective degeneration of cholinergic and dopaminergic neuronal populations are unclear, the action of neurotrophic substances in protecting and regenerating damaged neurons has recently received attention for its potential therapeutic role (see Phelps, 1989).BDNF promotes the survival and differentiation of fetal cholinergic neurons of the basal forebrain in vitro (Knusel et al, 1991;Nonomura and Hatanaka, 1992) as well as adult cholinergic neurons in vivo following septohippocampal transection Morse et al, 1993). BDNF also promotes the survival of fetal dopaminergic neurons and protects them from MPP + and 6-hydroxydopamine (6-OHDA) toxicity in vitro (Hyman et al, 1991;Beck et al, 1992;Spina et al, 1992;Hyman et al, 1994).…”

Basal forebrain cholinergic cell attachment and neurite outgrowth on organotypic slice cultures of hippocampal formation

“…However, it remains possible that the development of the cholinergic phenotype occurs preferentially in cells that have settled down in a supportive environment or have established appropriate adhesive contacts on the slice. Other studies have reported expression of the cholinergic phenotype in dissociated cultures (Dreyfus, 1989;Hartikka and Hefti, 1988;Li et al, 1995;Nonomura et al, 1996;Shingai et al, 1990), however, the presence of exogenously applied neurotrophic factors or the presence of normal target cells is important for expression of the cholinergic phenotype and for survival (Dreyfus, 1989;Ha et al, 1996;Hartikka and Hefti, 1988;Li et al, 1995;Morse et al, 1993;Nonomura et al, 1996;Shingai et al, 1990). Grown in isolation, without target contacts or supplemental neurotrophins, the BFCNs do not thrive.…”