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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
Author(s) -
Gustafsson Elin,
Andsberg Gunnar,
Darsalia Vladimer,
Mohapel Paul,
Mandel Ronald J.,
Kirik Deniz,
Lindvall Olle,
Kokaia Zaal
Publication year - 2003
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2003.02713.x
Subject(s) - neurotrophic factors , neuroscience , brain derived neurotrophic factor , neurotrophin , biology , ciliary neurotrophic factor , receptor , biochemistry
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, γ‐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.