Brain-derived neurotrophic factor in cerebral ischemia: a quantitative study on surviving and newly formed neurons

Sammanfattning: This study explores the role of brain-derived neurotrophic factor (BDNF) for neuronal vulnerability and neurogenesis following cerebral ischemia in the rat. Cerebral ischemia results in selective neuronal cell loss in specific brain regions. We here demonstrate the rank order of vulnerability in two regions affected by global forebrain ischemia, i.e., hippocampus and striatum, by combining specific immunocytochemical markers and stereological quantification methods. Furthermore, we found that the resistant cholinergic striatal interneurons increased their expression of the neurotrophin receptors p75NTR and TrkA, indicating a role for the neurotrophins for the cholinergic interneurons high resistance. By scavenging BDNF from the tissue we demonstrate that endogenous BDNF is neuroprotective for hippocampal CA4 pyramidal cells and NPY-positive hilar interneurons, and for striatal cholinergic interneurons. In contrast, when elevating the striatal BDNF levels by increasing the continuous anterograde transport from substantia nigra, we caused an increased vulnerability of NPY- and parvalbumin-immunoreactive as well as the cholinergic striatal interneurons. To explore the role of BDNF in ischemia-induced neurogenesis in the dentate gyrus, we transduced the hilus with a viral BDNF vector. The increased levels of BDNF resulted in a halted ischemia-induced neuronal differentiation in the dentate gyrus (DG), without affecting the survival of newly formed cells. To study this further, we scavenged BDNF from the hilus. The decreased levels of endogenous BDNF caused an increased number of newly formed neurons following the ischemic insult, demonstrating that both exogenous and endogenous BDNF can counteract the neuronal differentiation step. On the contrary, increasing the levels of BDNF via induced anterograde transport from the substantia nigra promoted stroke-induced neurogenesis in the striatum. Taken together these data reveal a remarkable diversity of BDNF in hippocampal and striatal cellular plasticity following cerebral ischemia.