Anterograde delivery of brain-derived neurotrophic factor to striatum via nigral transduction of recombinant adeno-associated virus increases neuronal death but promotes neurogenic response following stroke.
To explore the role of brain-derived neurotrophic factor for survival and generation of striatal neurons after stroke, recombinant adeno-associated viral vectors carrying brain-derived neurotrophic factor or green fluorescent protein genes were injected into right rat substantia nigra 4-5 weeks prior to 30 min ipsilateral of middle cerebral artery occlusion. The brain-derived neurotrophic factor-recombinant adeno-associated viral transduction markedly increased the production of brain-derived neurotrophic factor protein by nigral cells. Brain-derived neurotrophic factor was transported anterogradely to the striatum and released in biologically active form, as revealed by the hypertrophic response of striatal neuropeptide Y-positive interneurons. Animals transduced with brain-derived neurotrophic factor-recombinant adeno-associated virus also exhibited abnormalities in body posture and movements, including tilted body to the right, choreiform movements of left forelimb and head, and spontaneous, so-called 'barrel' rotation along their long axis. The continuous delivery of brain-derived neurotrophic factor had no effect on the survival of striatal projection neurons after stroke, but exaggerated the loss of cholinergic, and parvalbumin- and neuropeptide Y-positive, gamma-aminobutyric acid-ergic interneurons. The high brain-derived neurotrophic factor levels in the animals subjected to stroke also gave rise to an increased number of striatal cells expressing doublecortin, a marker for migrating neuroblasts, and cells double-labelled with the mitotic marker, 5-bromo-2'-deoxyuridine-5'monophosphate, and early neuronal (Hu) or striatal neuronal (Meis2) markers. Our findings indicate that long-term anterograde delivery of high levels of brain-derived neurotrophic factor increases the vulnerability of striatal interneurons to stroke-induced damage. Concomitantly, brain-derived neurotrophic factor potentiates the stroke-induced neurogenic response, at least at early stages.
Gustafsson
Elin
E
Section of Restorative Neurology, Wallenberg Neuroscience Center, University of Lund, BMC A-11 SE-221 84 Lund, Sweden.
Andsberg
Gunnar
G
Darsalia
Vladimer
V
Mohapel
Paul
P
Mandel
Ronald J
RJ
Kirik
Deniz
D
Lindvall
Olle
O
Kokaia
Zaal
Z
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002452:Cell Count; D016923:Cell Death; D048429:Cell Size / Q000502:physiology; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000473:pathology*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D051959:ELAV Proteins; D004569:Electroencephalography / Q000295:instrumentation / Q000379:methods; D004791:Enzyme Inhibitors / Q000633:toxicity; D004797:Enzyme-Linked Immunosorbent Assay; D049452:Green Fluorescent Proteins; D018398:Homeodomain Proteins / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D008164:Luminescent Proteins / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal / Q000295:instrumentation / Q000379:methods; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D009478:Neuropeptide Y / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000473:pathology*; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology; D014161:Transduction, Genetic / Q000379:methods; D019805:alpha-Methyltyrosine / Q000633:toxicity
D019208:Brain-Derived Neurotrophic Factor; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D051959:ELAV Proteins; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D009478:Neuropeptide Y; D009479:Neuropeptides; D010320:Parvalbumins; D016601:RNA-Binding Proteins; D011838:Radiation-Sensitizing Agents; D049452:Green Fluorescent Proteins; D019805:alpha-Methyltyrosine; D002795:Choline O-Acetyltransferase; D001973:Bromodeoxyuridine