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Differences in nigral neuron number and sensitivity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in C57/bl and
U Muthane1, K A Ramsay, H Jiang
1Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York 10032.
Abstract:
The present study demonstrates that the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes significantly greater reductions in striatal dopamine levels in C57/bl mice than in CD-1 mice, thus confirming a greater sensitivity of the C57/bl mice to MPTP. To determine the possible reasons for this difference in MPTP sensitivity between these two mouse strains, we have compared both the organization and the number of substantia nigra (SN) neurons, the primary target of MPTP, in C57/bl and in CD-1 mice using immunostaining for tyrosine hydroxylase (TH) and calbindin-D28k (calbindin). In saline-injected animals, there is a significantly lower number of SN TH-positive and calbindin-positive neurons in C57/bl than CD-1 mice; no significant differences in the numbers of these neurons are found in the ventral tegmental area between the two strains. In MPTP-injected animals, the reductions in SN TH-positive neurons are significantly greater in C57/bl than in CD-1 mice. In contrast, MPTP does not cause any significant changes in the numbers of SN calbindin-positive neurons in either strain. The present study shows that C57/bl mice which have fewer SN TH-positive neurons are more sensitive to MPTP-induced toxicity than CD-1 mice. This observation suggests a possible inverse relationship between SN TH-positive neuron number and MPTP sensitivity. If correct, this hypothesis may be of major importance for Parkinson's disease since it is suggested that individuals at risk of developing this neurodegenerative disorder may have lower numbers of SN TH-positive neurons to start with. The present study also shows that SN calbindin-positive neurons are spared following MPTP administration. However, the observed difference in SN calbindin-positive neuron numbers does not account for the differential sensitivity to MPTP between these two mouse strains.
Insights
C57/bl mice show greater sensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) than CD-1 mice, likely due to having fewer substantia nigra tyrosine hydroxylase-positive neurons. This suggests a potential link between lower neuron counts and increased MPTP toxicity.
Area of Science:
- Neuroscience
- Toxicology
- Neurodegenerative Diseases
Background:
- The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a widely used model to study Parkinson's disease pathogenesis.
- Differential sensitivity to MPTP exists across mouse strains, but the underlying mechanisms are not fully understood.
- Substantia nigra (SN) dopaminergic neurons are the primary targets of MPTP toxicity.
Purpose of the Study:
- To investigate the reasons for the differential sensitivity of C57/bl and CD-1 mice to MPTP.
- To compare the organization and number of substantia nigra neurons between C57/bl and CD-1 mice.
- To explore the relationship between SN neuron populations and MPTP-induced neurotoxicity.
Main Methods:
- Immunohistochemistry using tyrosine hydroxylase (TH) and calbindin-D28k (calbindin) staining.
- Quantification of TH-positive and calbindin-positive neurons in the substantia nigra (SN) and ventral tegmental area (VTA).
- Administration of MPTP or saline to C57/bl and CD-1 mice, followed by neuronal counting.
Main Results:
- C57/bl mice exhibited significantly greater reductions in striatal dopamine levels after MPTP exposure compared to CD-1 mice.
- Baseline SN TH-positive and calbindin-positive neuron counts were significantly lower in C57/bl mice than in CD-1 mice.
- MPTP caused greater loss of SN TH-positive neurons in C57/bl mice, while SN calbindin-positive neurons remained largely unaffected in both strains.
Conclusions:
- C57/bl mice, possessing fewer SN TH-positive neurons, are more susceptible to MPTP toxicity than CD-1 mice.
- An inverse relationship between SN TH-positive neuron number and MPTP sensitivity is suggested.
- This finding may have implications for understanding Parkinson's disease risk, potentially linked to pre-existing lower dopaminergic neuron counts.