Intraventricular infusion of TrkB-Fc fusion protein promotes ischemia-induced neurogenesis in adult rat dentate gyrus.
OBJECTIVE
We have previously shown that delivery of brain-derived neurotrophic factor (BDNF) through direct intrahippocampal gene transduction with a viral vector suppresses the formation of new dentate granule cells triggered by global forebrain ischemia. Here, we investigated whether inhibition of endogenous BDNF alters ischemia-induced neurogenesis in the dentate gyrus.


METHODS
Rats were subjected to 30 minutes of global forebrain ischemia and then received intraventricular infusion of either the BDNF scavenger, TrkB-Fc fusion protein, or control Hu-Fc for 2 weeks. In parallel, all animals were injected intraperitoneally with the mitosis marker 5-bromo-2'-deoxyuridine-5'-monophosphate (BrdU). Animals were killed at 2 or 6 weeks after the ischemic insult, and neurogenesis was then assessed immunocytochemically with epifluorescence or confocal microscopy.


RESULTS
Infusion of TrkB-Fc fusion protein gave rise to elevated numbers of ischemia-generated new neurons, double-labeled with BrdU and the early neuronal marker Hu or the mature neuronal marker NeuN, in the dentate subgranular zone and granule cell layer at 2 and 6 weeks after the insult.


CONCLUSIONS
Our findings provide evidence that endogenous BDNF counteracts neuronal differentiation, but not cell proliferation or survival, in ischemia-induced dentate gyrus neurogenesis.
Gustafsson
Elin
E
Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, Lund, Sweden.
Lindvall
Olle
O
Kokaia
Zaal
Z
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis; D002545:Brain Ischemia / Q000503:physiopathology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D001973:Bromodeoxyuridine; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D004195:Disease Models, Animal; D007141:Immunoglobulin Fc Fragments / Q000235:genetics*; D007276:Injections, Intraventricular; D008297:Male; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D016548:Prosencephalon / Q000098:blood supply / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*
D000943:Antigens, Differentiation; D019208:Brain-Derived Neurotrophic Factor; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D020813:Receptor, trkB; D001973:Bromodeoxyuridine