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

Sci Rep. 2019 Sep 9;9(1):12916. doi: 10.1038/s41598-019-49356-x.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Biomarkers
  • Cell Survival
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Disease Models, Animal
  • Excitatory Postsynaptic Potentials*
  • Glutamic Acid / metabolism
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Male
  • Neurodegenerative Diseases / diagnostic imaging
  • Neurodegenerative Diseases / etiology*
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Positron-Emission Tomography
  • Rats
  • Receptor, Metabotropic Glutamate 5 / genetics
  • Receptor, Metabotropic Glutamate 5 / metabolism*

Substances

  • Biomarkers
  • Grm5 protein, rat
  • Receptor, Metabotropic Glutamate 5
  • Glutamic Acid