Low dopamine transporter mRNA levels in midbrain regions containing calbindin
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M K Sanghera1, K F Manaye, C L Liang
1Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas 75235-9070.
Abstract:
The dopamine transporter (DAT) is the site at which the neurotoxic metabolite of MPTP gains access to midbrain dopaminergic (DA) neurons. However, not all midbrain DA neurons degenerate following MPTP treatment. The midbrain DA neurons that contain the calcium-binding protein, calbindin-D28k (CALB), are relatively invulnerable to MPTP toxicity, compared with DA neurons that lack CALB. Using in situ hybridization and immunocytochemical staining techniques in the rat and mouse, we now report that there is as much as 10 fold less DAT mRNA in regions where DA neurons contain CALB compared with regions where DA neurons lack CALB. These data suggest that specific midbrain DA neurons are invulnerable to MPTP toxicity not only because they contain CALB, but also because they have relatively low DAT activity.
Insights
Midbrain dopaminergic (DA) neurons containing calbindin-D28k (CALB) are protected from MPTP neurotoxicity. This invulnerability is linked to lower dopamine transporter (DAT) mRNA levels in these specific DA neurons.
Area of Science:
- Neuroscience
- Neurotoxicology
- Molecular Biology
Background:
- The neurotoxin MPTP targets midbrain dopaminergic (DA) neurons via the dopamine transporter (DAT).
- Not all DA neurons are equally susceptible to MPTP-induced degeneration.
- Calbindin-D28k (CALB)-containing DA neurons exhibit relative resistance to MPTP toxicity.
Purpose of the Study:
- To investigate the relationship between CALB expression and DAT levels in DA neurons.
- To understand the molecular mechanisms underlying differential MPTP vulnerability in midbrain DA neurons.
Main Methods:
- In situ hybridization to quantify DAT mRNA levels.
- Immunocytochemical staining to identify CALB-positive DA neurons.
- Comparative analysis in rat and mouse models.
Main Results:
- Regions with CALB-containing DA neurons showed significantly lower DAT mRNA levels (up to 10-fold less) compared to regions lacking CALB.
- This suggests a correlation between low DAT expression and CALB presence in resistant DA neurons.
Conclusions:
- CALB-containing DA neurons are protected from MPTP toxicity due to both the presence of CALB and reduced DAT activity.
- Lower DAT expression limits MPTP's access to these vulnerable neuronal populations.