Glutamate receptor binding sites in MPTP-treated mice
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Published on: January 7, 2014
U Wüllner1, E Brouillet, O Isacson
1Neurology Service, Massachusetts General Hospital, Boston 02114.
Abstract:
Changes in excitatory amino acid (EAA) neurotransmission are thought to play an important role in the development of parkinsonian symptoms. We examined EAA receptor binding sites in substantia nigra, striatum, globus pallidus, and cortex at 2 weeks and 2 months after MPTP (1-methyl-4-phenyl-1,2,3,6-tetra-hydroxypyridine) injection in C57bl6 mice. At 2 weeks striatal dopamine content in MPTP-treated mice was reduced to 7% of control and N-methyl-D-aspartate (NMDA)-sensitive [3H]glutamate and [3H]alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) binding sites were decreased in substantia nigra to 57 and 76% of control, respectively. In globus pallidus only [3H]AMPA binding sites were decreased to 80% of control; no significant changes were found in striatum or cortex. [3H]Kainate binding sites remained unchanged. At 2 months striatal dopamine content was reduced to 31% and no changes in EAA binding sites could be detected in any of the structures examined. [3H]Mazindol binding to striatal monoamine-uptake sites was decreased to 17% of control at 2 weeks versus 37% at 2 months. Our data indicate that modulation of NMDA and AMPA binding sites in substantia nigra and globus pallidus, the major projection areas of the subthalamic nucleus, takes place only after severe impairment of the nigrostriatal system.
Insights
Parkinsonian symptoms involve changes in excitatory amino acid (EAA) neurotransmission. Following MPTP-induced dopamine loss, N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor changes occur only after severe nigrostriatal impairment.
Area of Science:
- Neuroscience
- Neuropharmacology
- Parkinson's Disease Research
Background:
- Excitatory amino acid (EAA) neurotransmission is implicated in parkinsonian symptoms.
- MPTP (1-methyl-4-phenyl-1,2,3,6-tetra-hydroxypyridine) is a neurotoxin used to model Parkinson's disease.
Purpose of the Study:
- To investigate changes in EAA receptor binding sites in specific brain regions after MPTP injection.
- To determine the temporal relationship between dopamine depletion and EAA receptor modulation in a mouse model of Parkinson's disease.
Main Methods:
- MPTP injection in C57bl6 mice.
- Measurement of dopamine content in the striatum.
- Radioligand binding assays for glutamate, AMPA, and kainate receptors in substantia nigra, striatum, globus pallidus, and cortex at 2 weeks and 2 months post-injection.
- Assessment of monoamine-uptake sites using [3H]Mazindol.
Main Results:
- At 2 weeks post-MPTP, striatal dopamine was reduced to 7% of control.
- N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) binding sites decreased in the substantia nigra (57% and 76% of control, respectively).
- AMPA binding sites decreased in the globus pallidus (80% of control); no significant changes in striatum or cortex.
- At 2 months, dopamine was 31% of control, with no detected changes in EAA binding sites.
- [3H]Mazindol binding decreased to 17% at 2 weeks and 37% at 2 months.
Conclusions:
- Modulation of NMDA and AMPA binding sites in the substantia nigra and globus pallidus occurs only after severe impairment of the nigrostriatal system.
- These changes in EAA receptors are a late event in the progression of MPTP-induced parkinsonism.
