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Aberrant sprouting and downregulation of tyrosine hydroxylase in lesioned nigrostriatal dopamine neurons induced by long-lasting overexpression of glial cell line derived neurotrophic factor in the striatum by lentiviral gene transfer.
- Source :
-
Experimental neurology [Exp Neurol] 2002 Oct; Vol. 177 (2), pp. 461-74. - Publication Year :
- 2002
-
Abstract
- The effects of sustained (up to 9 months) striatal overexpression of glial cell line derived neurotrophic factor (GDNF) on lesioned nigrostriatal dopamine (DA) neurons was studied using a recombinant lentiviral (rLV) vector to deliver GDNF into the striatum 4 weeks prior to the creation of an intrastriatal 6-hydroxydopamine lesion. The results of the amphetamine-induced rotation suggested an initial partial protection followed by a complete recovery, whereas the spontaneous motor behaviors remained impaired. There was a clear protection of the nigral tyrosine hydroxylase (TH)-positive neurons in the rLV-GDNF group compared to rats injected with the control vector encoding green fluorescent protein (GFP) (70 and 20% of the intact side, respectively). However, the striatal TH+ fiber density was equally reduced (to 20% of the intact side) in both groups. Further morphological analyses indicated that the nigrostriatal projections of the DA neurons were indeed preserved in the GDNF group. The axonal projections were visualized using two independent methods: First, retrograde labeling of the nigral cell bodies by intrastriatal Fluoro-Gold injections showed that the majority of rescued cells in the GDNF group had preserved axonal projections to striatum. Second, injections of a recombinant adeno-associated viral vector expressing GFP into the nigra was used to anterogradely fill the DA neurons and their projections with GFP protein. GFP immunostaining clearly demonstrated that the fibers of the nigral DA cells were preserved along the nigrostriatal pathway and innervated large parts of the striatum, but did not express TH at detectable levels. In addition, fiber sprouting was observed in the globus pallidus, entopeduncular nucleus, and substantia nigra, corresponding to areas where GDNF protein was released. The lack of functional recovery in the spontaneous motor behaviors may, at least in part, be explained by this extensive aberrant fiber sprouting in the downstream striatal target nuclei and/or decreased synthesis of dopamine in the striatum.
- Subjects :
- Animals
Axons drug effects
Axons enzymology
Axons pathology
Behavior, Animal drug effects
Cell Count
Corpus Striatum enzymology
Disease Models, Animal
Down-Regulation
Female
Gene Transfer Techniques
Glial Cell Line-Derived Neurotrophic Factor
Green Fluorescent Proteins
Lentivirus genetics
Luminescent Proteins biosynthesis
Luminescent Proteins genetics
Motor Activity drug effects
Nerve Growth Factors genetics
Nerve Growth Factors pharmacology
Neural Pathways drug effects
Neural Pathways enzymology
Neural Pathways pathology
Oxidopamine
Parkinsonian Disorders chemically induced
Rats
Rats, Sprague-Dawley
Recovery of Function drug effects
Recovery of Function genetics
Substantia Nigra enzymology
Time
Tyrosine 3-Monooxygenase deficiency
Corpus Striatum pathology
Nerve Growth Factors biosynthesis
Parkinsonian Disorders physiopathology
Substantia Nigra pathology
Tyrosine 3-Monooxygenase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0014-4886
- Volume :
- 177
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Experimental neurology
- Publication Type :
- Academic Journal
- Accession number :
- 12429192
- Full Text :
- https://doi.org/10.1006/exnr.2002.8006