THE SURVIVAL-PROMOTING EFFECT OF GLIAL-CELL LINE-DERIVED NEUROTROPHICFACTOR ON AXOTOMIZED CORTICOSPINAL NEURONS IN-VIVO IS MEDIATED BY AN ENDOGENOUS BRAIN-DERIVED NEUROTROPHIC FACTOR MECHANISM

Autocrine trophic functions of brain-derived neurotrophic factor (BDNF ) have been proposed for many central neurons because this neurotrophi n displays striking colocalization with its receptor trkB within the C NS, In the cortex, the distribution patterns of BDNF and trkB expressi on are almost identical. Corticospinal neurons (CSNs) are a major cort ical long-distance projecting system. They are localized in layer V of the somatosensory cortex, and their axons project into the spinal cor d where they contribute to the innervation of spinal motoneurons. We h ave shown recently that adult CSNs express trkB mRNA and are rescued f rom axotomy-induced death by BDNF treatment. Half of the axotomized CS Ns survived without BDNF infusions. These findings raise the possibili ty that endogenous cortical BDNF is involved in the trophic support of this neuronal population. To test the hypothesis that endogenous cort ical BDNF promotes survival of adult CSNs, we infused the BDNF-neutral izing affinity-purified antibody RAB to axotomized and unlesioned CSNs for 7 d, This treatment resulted in increased death of axotomized CSN s, Survival of unlesioned CSNs was not affected by RAB treatment. In s itu hybridizations for BDNF and trkB mRNA revealed that virtually all CSNs express trkB, whereas only half of them express BDNF, Thus, autoc rine/paracrine mechanisms are likely to contribute to the endogenous B DNF protection of axotomized CSNs. We have demonstrated previously tha t, in addition to BDNF, glial cell line-derived neurotrophic factor (G DNF) and neurotrophin 3 (NT-3) also rescue CSNs from axotomy-induced d eath. We now show that the rescuing by GDNF requires the presence of e ndogenous cortical BDNF, implicating a central role of this neurotroph in in the trophic support of axotomized CSNs and a trophic cross-talk between BDNF and GDNF regarding the maintenance of lesioned CSNs. In c ontrast, NT-3 promotes survival of axotomized CSNs even when endogenou s cortical BDNF is neutralized by RAB, indicating a potential of compe nsatory mechanisms for the trophic support of CSNs.