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Published on: April 29, 2017
Excitotoxic neurodegeneration is associated with a focal decrease in metabotropic glutamate receptor type 5
Melissa Crabbé1,2, Nina Dirkx3,4, Cindy Casteels3,4
1Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium. crabbe.melissa@outlook.com.
Abstract:
Metabotropic glutamate receptors (mGluRs) have been proposed as promising therapeutic targets to correct the dysregulated glutamate signaling, associated with neurodegenerative pathologies. Of all mGluR subtypes, especially mGluR5 acts as a modulator of glutamate-induced excitotoxicity. To study the behavior of mGluR5 following localized excitotoxicity, we utilised a pharmacological model that portrays exacerbated neuronal glutamate release, mediated by the endogenous excitotoxin quinolinic acid (QA). Using longitudinal positron emission tomography (PET) with [18F]FPEB, we investigated cerebral changes in mGluR5 following striatal QA-lesioning. Behavioral tests were executed to monitor motor and cognitive performance. Decreased mGluR5 binding potential (BPND) was found in the affected striatum and globus pallidus of QA-lesioned rats at week 3, and further decreased at week 7, as compared to sham-injected controls. mGluR5 availability in the ipsilateral nucleus accumbens was significantly decreased at 7 weeks post-injection. QA rats performed significantly worse on motor coordination and balance compared to control rats. Correlation analysis indicated a positive correlation between striatal mGluR5 BPND and rotarod performance whereas print width of the unaffected forepaws showed a positive relation with mGluR5 BPND in the contralateral motor cortex. Together, our results suggest decreased mGluR5 availability to be related to excitotoxin-induced neurodegeneration and symptomatology although late stage effects do indicate possible cortical mGluR5-mediated effects on motor behavior.
Insights
This study shows that metabotropic glutamate receptor 5 (mGluR5) availability decreases after excitotoxicity, impacting motor function in rats. Reduced mGluR5 binding correlates with neurodegeneration and behavioral deficits.
Area of Science:
- Neuroscience
- Pharmacology
- Radiochemistry
Background:
- Metabotropic glutamate receptors (mGluRs) are implicated in neurodegenerative diseases due to their role in regulating glutamate signaling.
- mGluR5 specifically modulates glutamate-induced excitotoxicity, making it a potential therapeutic target.
- Understanding mGluR5 dynamics in neurodegeneration is crucial for developing effective treatments.
Purpose of the Study:
- To investigate changes in metabotropic glutamate receptor 5 (mGluR5) availability in a rat model of localized excitotoxicity induced by quinolinic acid (QA).
- To correlate these changes with motor and cognitive behavioral deficits.
- To assess the potential of mGluR5 as a biomarker and therapeutic target in excitotoxic neurodegeneration.
Main Methods:
- Utilized a pharmacological model of excitotoxicity using quinolinic acid (QA) in rats.
- Employed longitudinal positron emission tomography (PET) with [18F]FPEB to quantify mGluR5 binding potential (BPND).
- Conducted behavioral tests, including rotarod, to assess motor coordination and balance.
Main Results:
- Decreased mGluR5 BPND was observed in the striatum and globus pallidus of QA-lesioned rats at 3 and 7 weeks post-lesioning.
- Significant reduction in mGluR5 availability was noted in the nucleus accumbens at 7 weeks.
- QA-lesioned rats exhibited impaired motor performance, with striatal mGluR5 BPND positively correlating with rotarod performance.
Conclusions:
- Excitotoxin-induced neurodegeneration is associated with decreased mGluR5 availability in specific brain regions.
- Reduced mGluR5 levels correlate with motor deficits, suggesting its role in excitotoxicity-related symptomatology.
- Late-stage effects hint at potential cortical mGluR5 involvement in motor behavior, warranting further investigation.
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