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.
Highlights
Glutamate is the dominant excitatory neurotransmitter in the brain and plays a crucial role in the central nervous system (CNS) by acting through two types of receptors, the ionotropic and metabotropic glutamate receptors
MGluR5 may act as a co-receptor to mutant huntingtin, amyloid-β plaques and α-synuclein oligomers, providing a direct link between mGluR5 and proteinopathies12–14. mGluR5 activation may facilitate the activation of NMDA receptors through the Homer/PSD95/Shank protein complex in dendritic spines, and this way play a permissive role in neuronal excitotoxicity[15]
Regional [18F]FPEB uptake is high in the striatum, hippocampus, and cortex, in accordance with the known brain distribution of mGluR520,27
Summary
Glutamate is the dominant excitatory neurotransmitter in the brain and plays a crucial role in the central nervous system (CNS) by acting through two types of receptors, the ionotropic (iGluR) and metabotropic (mGluR) glutamate receptors. Chronic glutamate-mediated neurotoxicity through overstimulation of iGluRs (such as the N-methyl-D-aspartate (NMDA) receptor), and mGluRs, has been implicated in the disease onset and progression of several neurodegenerative diseases[3,4,5]. The receptor may be centrally involved in neurodegenerative movement disorders[7,8]. MGluR5 activation may facilitate the activation of NMDA receptors through the Homer/PSD95/Shank protein complex in dendritic spines, and this way play a permissive role in neuronal excitotoxicity[15]. The topographical organization of neuronal mGluR5 expression is restricted to cerebral regions affected by neurodegenerative diseases, such as the striatum, cerebral cortex and hippocampus[20]. The effect of excitotoxicity and subsequent post-synaptic dysfunction of striatal medium spiny neurons (MSN) on mGluR5 availability has not been researched yet. We investigated the effect of QA lesioning on regional mGluR5 levels in vivo, employing 3-[18F]-fluoro5-(2-pyridinylethynyl) benzonitrile ([18F]FPEB) microPET in relation to behavioral measures and immunohistochemistry
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