The Survival-Promoting Effect of Glial Cell Line-Derived Neurotrophic Factor on Axotomized Corticospinal NeuronsIn VivoIs Mediated by an Endogenous Brain-Derived Neurotrophic Factor Mechanism

Abstract

Autocrine trophic functions of brain-derived neurotrophic factor (BDNF) have been proposed for many central neurons because this neurotrophin displays striking colocalization with its receptor trkB within the CNS. In the cortex, the distribution patterns of BDNF and trkB expression are almost identical. Corticospinal neurons (CSNs) are a major cortical long-distance projecting system. They are localized in layer V of the somatosensory cortex, and their axons project into the spinal cord where they contribute to the innervation of spinal motoneurons. We have shown recently that adult CSNs express trkB mRNA and are rescued from axotomy-induced death by BDNF treatment. Half of the axotomized CSNs survived without BDNF infusions. These findings raise the possibility that endogenous cortical BDNF is involved in the trophic support of this neuronal population. To test the hypothesis that endogenous cortical BDNF promotes survival of adult CSNs, we infused the BDNFneutralizing affinity-purified antibody RAB to axotomized and unlesioned CSNs for 7 d. This treatment resulted in increased death of axotomized CSNs. Survival of unlesioned CSNs was not affected by RAB treatment. In situ hybridizations for BDNF and trkB mRNA revealed that virtually all CSNs express trkB, whereas only half of them express BDNF. Thus, autocrine/ paracrine mechanisms are likely to contribute to the endogenous BDNF protection of axotomized CSNs. We have demonstrated previously that, in addition to BDNF, glial cell linederived neurotrophic factor (GDNF) and neurotrophin 3 (NT-3) also rescue CSNs from axotomy-induced death. We now show that the rescuing by GDNF requires the presence of endogenous cortical BDNF, implicating a central role of this neurotrophin in the trophic support of axotomized CSNs and a trophic cross-talk between BDNF and GDNF regarding the maintenance of lesioned CSNs. In contrast, NT-3 promotes survival of axotomized CSNs even when endogenous cortical BDNF is neutralized by RAB, indicating a potential of compensatory mechanisms for the trophic support of CSNs.

Secreted proNGF is a pathophysiological death-inducing ligand after adult CNS injury

“…This result is similar to what we have reported by using spinal-cord injury as a model, in which BDNF and NT3 levels did not change with the injury, whereas NGF level increased dramatically (3). These data are consistent also with our earlier reports in which BDNF (14,17) and NT3 (data not shown) message levels did not change after the CSN lesion. These results strongly suggest that proNGF, but not proBDNF or proNT-3, is secreted into the CSF.…”

“…Of the neurotrophin receptors, p75 is the only receptor whose mRNA expression is dramatically induced in lesioned CSN, whereas Trk receptor expression remains unchanged (5,14). In agreement with in situ hybridization data (5), p75 protein was undetectable in the unlesioned cortex, but beginning 1 d after internal-capsule lesion, it was present in the lesioned cortex and reached highest levels by 3 d after lesion (Fig.…”

“…Consistent with their responses to BDNF and NT3, CSN express TrkB and TrkC, but not TrkA (7,14). Of the neurotrophin receptors, p75 is the only receptor whose mRNA expression is dramatically induced in lesioned CSN, whereas Trk receptor expression remains unchanged (5,14).…”

“…During embryonic development, neurotrophin 3 (NT3) promotes differentiation of cortical precursors into brainderived neurotrophic factor (BDNF)-dependent neurons in culture (12,13). When fully differentiated, these neurons adopt the adult phenotype and lose these trophic requirements (5,14). After axotomy at internal capsule levels, the survival of adult CSN is again regulated by endogenous neurotrophins, with BDNF supporting survival, whereas NT3 promotes death of BDNF-dependent CSN (5,14).…”

“…When fully differentiated, these neurons adopt the adult phenotype and lose these trophic requirements (5,14). After axotomy at internal capsule levels, the survival of adult CSN is again regulated by endogenous neurotrophins, with BDNF supporting survival, whereas NT3 promotes death of BDNF-dependent CSN (5,14). NT3, however, appears to act by means of an indirect mechanism and not by activating its own death program.…”