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

To evaluate effective means for delivering exogenous neurotrophins to neuron populations in the brain, we compared the distribution and tran sport of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and neurotrophin-3 (NT-3) following intracerebral delivery. Ra ts received an injection of radioiodinated or unlabeled neurotrophin i nto the lateral ventricle and were killed humanely after 1.5-24 hours. Other rats received continuous infusion of unlabeled neurotrophin int o the lateral ventricle, the striatum, or the hippocampus for 3-14 day s. The neurotrophins were detected by autoradiography or immunohistoch emistry. There were striking differences between BDNF, NGF, and NT-3 i n their penetration through brain tissue. These differences occurred r egardless of the site or method of delivery, but were most pronounced following a bolus intracerebroventricular (ICV) injection. After ICV i njection, 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 rece ptor, whereas an injection of BDNF prominently labeled the ventricular ependyma. During ICV infusion (12 mu g/day), the distribution of BDNF was no greater than that observed after a 12-mu g bolus injection. A sixfold increase in the amount of BDNF infused (72 mu g/day) produced a more widespread distribution in the brain and doubled the depth of p enetration into periventricular tissues near the cannula. Correspondin g to their differences in penetration, NGF was retrogradely transporte d by basal forebrain cholinergic neurons after ICV or intrastriatal de livery, 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 s itu hybridization studies confirmed that the high-affinity BDNF recept or (TrkB) was much more widely expressed in neurons than was the high- affinity NGF receptor (TrkA). Moreover, mRNA for truncated forms of Tr kB was expressed at high levels in the ependyma, the choroid epitheliu m, and the gray matter. It is likely that binding of BDNF to TrkB, whi ch appears to be more abundant and ubiquitous than TrkA, restricts the diffusion of BDNF relative to that of NGF. (C) 1995 Wiley-Liss, Inc.