Differential distribution of exogenous BDNF, NGF, and NT‐3 in the brain corresponds to the relative abundance and distribution of high‐affinity and low‐affinity neurotrophin receptors

Abstract

To evaluate effective means for delivering exogenous neurotrophins to neuron populations in the brain, we compared the distribution and transport of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) following intracerebral delivery. Rats received an injection of radioiodinated or unlabeled neurotrophin into the lateral ventricle and were killed humanely after 1.5-24 hours. Other rats received continuous infusion of unlabeled neurotrophin into the lateral ventricle, the striatum, or the hippocampus for 3-14 days. The neurotrophins were detected by autoradiography or immunohistochemistry. There were striking differences between BDNF, NGF, and NT-3 in their penetration through brain tissue. These differences occurred regardless of the site or method of delivery, but were most pronounced following a bolus intracerebroventricular (ICV) injection. After ICV injection, NGF was widely distributed in tissues around the ventricles and at the surface of the brain, whereas the penetration of BDNF into brain tissue was distinctly less than that of NGF, and the penetration of NT-3 was intermediate. An ICV injection of NGF produced prominent but transient labeling of cells that contain the low-affinity NGF receptor, whereas an injection of BDNF prominently labeled the ventricular ependyma. During ICV infusion (12 micrograms/day), the distribution of BDNF was no greater than that observed after a 12-micrograms bolus injection. A sixfold increase in the amount of BDNF infused (72 micrograms/day) produced a more widespread distribution in the brain and doubled the depth of penetration into periventricular tissues near the cannula. Corresponding to their differences in penetration, NGF was retrogradely transported by basal forebrain cholinergic neurons after ICV or intrastriatal delivery, whereas NT-3 was transported by a few basal forebrain neurons after ICV delivery, and BDNF was rarely detected in neurons after ICV delivery. Delivery of BDNF directly to the striatum or the hippocampus labeled numerous neurons in nuclei afferent to these structures. In situ hybridization studies confirmed that the high-affinity BDNF receptor (TrkB) was much more widely expressed in neurons than was the high-affinity NGF receptor (TrkA). Moreover, mRNA for truncated forms of TrkB was expressed at high levels in the ependyma, the choroid epithelium, and the gray matter. It is likely that binding of BDNF to TrkB, which appears to be more abundant and ubiquitous than TrkA, restricts the diffusion of BDNF relative to that of NGF.

Expression of Neurotrophin-3 (NT-3) and Anterograde Axonal Transport of Endogenous NT-3 by Retinal Ganglion Cells in Chick Embryos

“…1 A). Therefore, the monoclonal NT-3 antibody is as sensitive and specific as other neurotrophin antibodies that have been characterized previously (Zhou and Rush, 1993;Anderson et al, 1995).…”

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…BDNF and its receptor TrkB are co-expressed in serotonergic neurons within the dorsal raphe and median raphe (Merlio et al, 1992;Madhav et al, 2001), and BDNF is retrogradely transported from 5-HT terminals in the striatum and hippocampus to cell bodies in the raphe nuclei (Anderson et al, 1995). BDNF has been shown to promote the survival and morphological differentiation of 5-HT neurons both in culture and in vivo.…”

Neuregulins, Neuroprotection and Parkinson's Disease

“…Both trkB and trkC mRNAs are broadly distributed at moderate levels within numerous striatal neurons (6,9,119,130). Immunoreactivlty for trkB is also observed in the striatum, as well as in other regions of adult rat brain (204).…”

“…BDNF protein, however, is found in the striatum and appears to be transported anterogradely to the striatum pia several afferent pathways: corticostriatal, nigrostriatal, amygdalostriatal, thalamostriatal (8,39). Nigral neurons also exhibit specific retrograde axonal transport of BDNF and NT-3, but not NGF, from the striatum (9,124). BDNF protein levels in the striatum of young adult rats are approximately 5-7 ng/g tissue as measured by ELISA (126,212,219).…”