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Excitotoxic neurodegeneration is associated with a focal decrease in metabotropic glutamate receptor type 5 availability: an in vivo PET imaging study

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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.
Tijdschrift: Scientific Reports
ISSN: 2045-2322
Issue: 1
Volume: 9
Jaar van publicatie:2019
BOF-keylabel:ja
IOF-keylabel:ja
BOF-publication weight:2
CSS-citation score:1
Authors from:Higher Education
Toegankelijkheid:Open