Nigrostriatal alterations in bone morphogenetic protein receptor II dominant negative mice.
BACKGROUND
We previously demonstrated that exogenous application of bone morphogenetic protein 7 (BMP7) reduced 6-hydroxydopamine-mediated neurodegeneration in a rodent model of Parkinson's disease. The purpose of this study is to examine the endogenous neurotrophic properties of BMP Receptor II in dopaminergic neurons of the nigrostriatal pathway.


METHODS
Adult male BMPRII dominant negative (BMPRIIDN) mice and their wild type controls (WT) were placed in the activity chambers for 3 days to monitor locomotor activity. Animals were sacrificed for tyrosine hydroxylase (TH) immunostaining. A subgroup of BMPRIIDN and WT mice were injected with high doses of methamphetamine (MA) and were sacrificed for terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) histochemistry at 4 days after injection.


RESULTS
BMPRIIDN mice had lower locomotor activity than the WT. There is a significant decrease in TH neuronal number in substantia nigra compacta, TH fiber density in the substantia nigra reticulata, and TH immunoreactivity in striatum in the BMPRIIDN mice, suggesting that deficiency in endogenous BMP signaling reduces dopaminergic innervation and motor function in the nigrostriatal pathway. Administration of MA increased TUNEL labeling in the substantia nigra in the BMPRIIDN mice.


CONCLUSIONS
Endogenous BMPs have trophic effects on nigrostriatal dopaminergic neurons. Deficiency in BMP signaling increases vulnerability to insults induced by high doses of MA.
Chou
J
J
Neural Protection and Regeneration Section, National Institute on Drug Abuse, NIH, MD 21224, USA.
Harvey
B K
BK
Ebendal
T
T
Hoffer
B
B
Wang
Y
Y
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000172:deficiency / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013378:Substantia Nigra / Q000378:metabolism* / Q000473:pathology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II