Top

Published in:

Open Access 01-06-2010 | Basic Neurosciences, Genetics and Immunology - Original Article

Aged Tgfβ2/Gdnf double-heterozygous mice show no morphological and functional alterations in the nigrostriatal system

Authors: Stephan Heermann, Felipe Opazo, Björn Falkenburger, Kerstin Krieglstein, Björn Spittau

Published in: Journal of Neural Transmission | Issue 6/2010

Abstract

Loss of dopaminergic neurons in the substantia nigra pars compacta and the resulting decrease in striatal dopamine levels are the hallmarks of Parkinson’s disease. Tgfβ and Gdnf have been identified as neurotrophic factors for dopaminergic midbrain neurons in vivo and in vitro. Haploinsufficiency for either Tgfβ or Gdnf led to dopaminergic deficits. In this study we therefore analyzed the nigrostriatal system of aged Tgfβ2 ^+/−/Gdnf ^+/− double-heterozygous mice. Unexpectedly, we found no morphological changes in the nigrostriatal system as compared with age-matched wild-type mice. There were no significant differences in the number of TH-positive midbrain neurons and no changes in the optical density of TH immunoreactivity in striata of Tgfβ2 ^+/−/Gdnf ^+/− double-heterozygous mice. Moreover, we found no significant differences in the striatal levels of dopamine and its metabolites dihydroxyphenylacetic acid and homovanillic acid. Our results indicate that a combined haploinsufficiency for Tgfβ2 and Gdnf has no impact on the function and the survival of midbrain DA neurons under normal aging conditions.

Adams JC (1981) Heavy metal intensification of DAB-based HRP reaction product. J Histochem Cytochem 29:775PubMed

Andrews ZB, Zhao H, Frugier T, Meguro R, Grattan DR, Koishi K, McLennan IS (2006) Transforming growth factor beta2 haploinsufficient mice develop age-related nigrostriatal dopamine deficits. Neurobiol Dis 21:568–575CrossRefPubMed

Boger HA, Middaugh LD, Huang P, Zaman V, Smith AC, Hoffer BJ, Tomac AC, Granholm A (2006) A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra. Exp Neurol 202:336–347CrossRefPubMed

Bowenkamp KE, Hoffman AF, Gerhardt GA, Henry MA, Biddle PT, Hoffer BJ, Granholm AC (1995) Glial cell line-derived neurotrophic factor supports survival of injured midbrain dopaminergic neurons. J Comp Neurol 355:479–489CrossRefPubMed

Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909CrossRefPubMed

Farkas LM, Dünker N, Roussa E, Unsicker K, Krieglstein K (2003) Transforming growth factor-beta(s) are essential for the development of midbrain dopaminergic neurons in vitro and in vivo. J Neurosci 23:5178–5186PubMed

Gundersen HJ, Bagger P, Bendtsen TF, Evans SM, Korbo L, Marcussen N, Møller A, Nielsen K, Nyengaard JR, Pakkenberg B (1988) The new stereological tools: dissector, fractionator, nucleator and point sampled intercepts and their use in pathological research and diagnosis. APMIS 96:857–881CrossRefPubMed

Hoffer BJ, Hoffman A, Bowenkamp K, Huettl P, Hudson J, Martin D, Lin LF, Gerhardt GA (1994) Glial cell line-derived neurotrophic factor reverses toxin-induced injury to midbrain dopaminergic neurons in vivo. Neurosci Lett 182:107–111CrossRefPubMed

Jain S, Golden JP, Wozniak D, Pehek E, Johnson EM Jr, Milbrandt J (2006) Ret is dispensable for maintenance of midbrain dopaminergic neurons in adult mice. J Neurosci 26:11230–11238CrossRefPubMed

Kearns CM, Gash DM (1995) GDNF protects nigral dopamine neurons against 6-hydroxydopamine in vivo. Brain Res 672:104–111CrossRefPubMed

Kordower JH, Emborg ME, Bloch J, Ma SY, Chu Y, Leventhal L, McBride J, Chen EY, Palfi S, Roitberg BZ, Brown WD, Holden JE, Pyzalski R, Taylor MD, Carvey P, Ling Z, Trono D, Hantraye P, Déglon N, Aebischer P (2000) Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson’s disease. Science 290:767–773CrossRefPubMed

Kowsky S, Pöppelmeyer C, Kramer ER, Falkenburger BH, Kruse A, Klein R, Schulz JB (2007) RET signaling does not modulate MPTP toxicity but is required for regeneration of dopaminergic axon terminals. Proc Natl Acad Sci USA 104:20049–20054CrossRefPubMed

Kramer ER, Aron L, Ramakers GM, Seitz S, Zhuang X, Beyer K, Smidt MP, Klein R (2007) Absence of ret signaling in mice causes progressive and late degeneration of the nigrostriatal system. PLoS Biol 5:e39CrossRefPubMed

Krieglstein K, Unsicker K (1994) Transforming growth factor-beta promotes survival of midbrain dopaminergic neurons and protects them against N-methyl-4-phenylpyridinium ion toxicity. Neuroscience 63:1189–1196CrossRefPubMed

Krieglstein K, Suter-Crazzolara C, Fischer WH, Unsicker K (1995) TGF-beta superfamily members promote survival of midbrain dopaminergic neurons and protect them against MPP+ toxicity. EMBO J 14:736–742PubMed

Krieglstein K, Henheik P, Farkas L, Jaszai J, Galter D, Krohn K, Unsicker K (1998) Glial cell line-derived neurotrophic factor requires transforming growth factor-beta for exerting its full neurotrophic potential on peripheral and CNS neurons. J Neurosci 18:9822–9834PubMed

Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F (1993) GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260:1130–1132CrossRefPubMed

Peterziel H, Unsicker K, Krieglstein K (2002) TGFbeta induces GDNF responsiveness in neurons by recruitment of GFRalpha1 to the plasma membrane. J Cell Biol 159:157–167CrossRefPubMed

Pichel JG, Shen L, Sheng HZ, Granholm AC, Drago J, Grinberg A, Lee EJ, Huang SP, Saarma M, Hoffer BJ, Sariola H, Westphal H (1996) Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382:73–76CrossRefPubMed

Rahhal B, Heermann S, Ferdinand A, Rosenbusch J, Rickmann M, Krieglstein K (2009) In vivo requirement of TGF-beta/GDNF cooperativity in mouse development: focus on the neurotrophic hypothesis. Int J Dev Neurosci 27:97–102CrossRefPubMed

Roussa E, Oehlke O, Rahhal B, Heermann S, Heidrich S, Wiehle M, Krieglstein K (2008) Transforming growth factor beta cooperates with persephin for dopaminergic phenotype induction. Stem Cells 26:1683–1694CrossRefPubMed

Sánchez MP, Silos-Santiago I, Frisén J, He B, Lira SA, Barbacid M (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382:70–73CrossRefPubMed

Sanford LP, Ormsby I, Gittenberger-de Groot AC, Sariola H, Friedman R, Boivin GP, Cardell EL, Doetschman T (1997) TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes. Development 124:2659–2670PubMed

Sauer H, Rosenblad C, Björklund A (1995) Glial cell line-derived neurotrophic factor but not transforming growth factor beta 3 prevents delayed degeneration of nigral dopaminergic neurons following striatal 6-hydroxydopamine lesion. Proc Natl Acad Sci USA 92:8935–8939

Schober A, Peterziel H, von Bartheld CS, Simon H, Krieglstein K, Unsicker K (2007) GDNF applied to the MPTP-lesioned nigrostriatal system requires TGF-beta for its neuroprotective action. Neurobiol Dis 25:378–391CrossRefPubMed

Tomac A, Lindqvist E, Lin LF, Ogren SO, Young D, Hoffer BJ, Olson L (1995) Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373:335–339CrossRefPubMed

Title: Aged Tgfβ2/Gdnf double-heterozygous mice show no morphological and functional alterations in the nigrostriatal system
Authors: Stephan Heermann
Felipe Opazo
Björn Falkenburger
Kerstin Krieglstein
Björn Spittau
Publication date: 01-06-2010
Publisher: Springer Vienna
Published in: Journal of Neural Transmission / Issue 6/2010
Print ISSN: 0300-9564
Electronic ISSN: 1435-1463
DOI: https://doi.org/10.1007/s00702-010-0406-7

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Aged Tgfβ2/Gdnf double-heterozygous mice show no morphological and functional alterations in the nigrostriatal system

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2010

The sympathetic-vagal balance against endotoxemia

Associations between the serotonin-1A receptor C(-1019)G polymorphism and disordered eating symptoms in female adolescents

Impact of psychostimulants and atomoxetine on the expression of 8-hydroxyguanine glycosylase 1 in human cells

Cytoprotective effect of (−)-deprenyl, (−)desmethyl-deprenyl and (−)deprenyl-N-oxide on glutathione depleted A-2058 melanoma cells

Hemifacial spasm and reinnervation synkinesias: long-term treatment with either Botox® or Dysport®

Hemifacial spasm non-motor and motor-related symptoms and their response to botulinum toxin therapy