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

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Melissa Crabbé ◽  
Nina Dirkx ◽  
Cindy Casteels ◽  
Koen Van Laere
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Motor Coordination ◽  
Metabotropic Glutamate Receptor ◽  
Motor Behavior ◽  
Glutamate Release ◽  
Imaging Study ◽  
Binding Potential ◽  
Metabotropic Glutamate ◽  
Positron Emission

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.

scholarly journals Elevated Type 1 Metabotropic Glutamate Receptor Availability in a Mouse Model of Huntington’s Disease: a Longitudinal PET Study

2020 ◽  
Vol 57 (4) ◽  
pp. 2038-2047 ◽  
Author(s):  
Daniele Bertoglio ◽  
Jeroen Verhaeghe ◽  
Špela Korat ◽  
Alan Miranda ◽  
Klaudia Cybulska ◽  
...  
Keyword(s):  
Mouse Model ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Pet Imaging ◽  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Post Mortem ◽  
Metabotropic Glutamate ◽  
Group I

AbstractImpairment of group I metabotropic glutamate receptors (mGluRs) results in altered glutamate signalling, which is associated with several neurological disorders including Huntington’s Disease (HD), an autosomal neurodegenerative disease. In this study, we assessed in vivo pathological changes in mGluR1 availability in the Q175DN mouse model of HD using longitudinal positron emission tomography (PET) imaging with the radioligand [11C]ITDM. Ninety-minute dynamic PET imaging scans were performed in 22 heterozygous (HET) Q175DN mice and 22 wild-type (WT) littermates longitudinally at 6, 12, and 16 months of age. Analyses of regional volume of distribution with an image-derived input function (VT (IDIF)) and voxel-wise parametric VT (IDIF) maps were performed to assess differences between genotypes. Post-mortem evaluation at 16 months was done to support in vivo findings. [11C]ITDM VT (IDIF) quantification revealed higher mGluR1 availability in the brain of HET mice compared to WT littermates (e.g. cerebellum: + 15.0%, + 17.9%, and + 17.6% at 6, 12, and 16 months, respectively; p < 0.001). In addition, an age-related decline in [11C]ITDM binding independent of genotype was observed between 6 and 12 months. Voxel-wise analysis of parametric maps and post-mortem quantifications confirmed the elevated mGluR1 availability in HET mice compared to WT littermates. In conclusion, in vivo measurement of mGluR1 availability using longitudinal [11C]ITDM PET imaging demonstrated higher [11C]ITDM binding in extra-striatal brain regions during the course of disease in the Q175DN mouse model.

Activation of group II metabotropic glutamate receptors inhibits glutamate release from salamander retinal photoreceptors

2002 ◽  
Vol 19 (3) ◽  
pp. 275-281 ◽  
Author(s):  
MATTHEW H. HIGGS ◽  
PETER D. LUKASIEWICZ
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Ganglion Cells ◽  
Glutamate Release ◽  
Bipolar Cells ◽  
Horizontal Cells ◽  
Inward Current ◽  
Metabotropic Glutamate ◽  
Retinal Photoreceptors ◽  
Group Ii

We investigated the effects of group II metabotropic glutamate receptor (mGluR) activation on excitatory synaptic transmission in the salamander retinal slice preparation. The group II selective agonists DCG-IV and LY354740 reduced light-evoked excitatory postsynaptic currents (EPSCs) in ganglion cells. To determine the synaptic basis of this effect, we also recorded from bipolar cells and horizontal cells. In ON bipolar cells, DCG-IV increased the inward current in darkness but did not affect the peak current at light onset. In OFF bipolar cells and horizontal cells, DCG-IV had the opposite effect, reducing the inward current in darkness. Given the opposite polarities of these two classes of synapses, our results suggest that group II mGluRs act presynaptically to reduce glutamate release from photoreceptors. To determine whether DCG-IV affected rods or cones, we applied light stimuli that selectively activate each type of photoreceptor. In horizontal cells, most of which receive mixed synaptic input from rods and cones, DCG-IV reduced rod-driven EPSCs evoked by 470-nm stimuli and cone-driven EPSCs elicited by 700-nm stimuli in the presence of a rod-saturating background. Thus, activation of group II mGluRs reduced rod- and cone-mediated glutamate release. Our results suggest that group II mGluRs could mediate feedback by which extracellular glutamate inhibits glutamate release from photoreceptor terminals.

scholarly journals In vivo variation in same-day estimates of metabotropic glutamate receptor subtype 5 binding using [11C]ABP688 and [18F]FPEB

2016 ◽  
Vol 37 (8) ◽  
pp. 2716-2727 ◽  
Author(s):  
Christine DeLorenzo ◽  
Jean-Dominique Gallezot ◽  
John Gardus ◽  
Jie Yang ◽  
Beata Planeta ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Emission Tomography ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Positron Emission ◽  
Absolute Test ◽  
Residual Radioactivity

Positron emission tomography tracers [11C]ABP688 and [18F]FPEB target the metabotropic glutamate receptor subtype 5 providing quantification of the brain glutamatergic system in vivo. Previous [11C]ABP688 positron emission tomography human test–retest studies indicate that, when performed on the same day, significant binding increases are observed; however, little deviation is reported when scans are >7 days apart. Due to the small cohorts examined previously (eight and five males, respectively), we aimed to replicate the same-day test–retest studies in a larger cohort including both males and females. Results confirmed large within-subject binding differences (ranging from −23% to 108%), suggesting that measurements are greatly affected by study design. We further investigated whether this phenomenon was specific to [11C]ABP688. Using [18F]FPEB and methodology that accounts for residual radioactivity from the test scan, four subjects were scanned twice on the same day. In these subjects, binding estimates increased between 5% and 39% between scans. Consistent with [11C]ABP688, mean absolute test–retest variability was previously reported as <12% when scans were >21 days apart. This replication study and pilot extension to [18F]FPEB suggest that observed within-day binding variation may be due to characteristics of mGluR5; for example, diurnal variation in mGluR5 may affect measurement of this receptor.

scholarly journals Acute Ketamine Infusion in Rat Does Not Affect In Vivo [11C]ABP688 Binding to Metabotropic Glutamate Receptor Subtype 5

2018 ◽  
Vol 17 ◽  
pp. 153601211878863 ◽  
Author(s):  
Lauren Kosten ◽  
Jeroen Verhaeghe ◽  
Leonie wyffels ◽  
Sigrid Stroobants ◽  
Steven Staelens
Keyword(s):  
Nmda Receptor ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Glutamate Release ◽  
Acute Effect ◽  
Receptor Subtype ◽  
Ketamine Infusion ◽  
Metabotropic Glutamate ◽  
Pet Tracer

Detecting changes in metabotropic glutamate receptor 5 (mGluR5) availability through molecular imaging with the positron emission tomography (PET) tracer [11C]ABP688 is valuable for studying dysfunctional glutamate transmission associated with neuropsychiatric disorders. Using an infusion protocol in rats, we visualized the acute effect of subanesthetic doses of ketamine on mGluR5 in rat brain. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist known to increase glutamate release. Imaging was performed with a high-affinity PET ligand [11C]ABP688, a negative allosteric modulator of mGluR5. Binding did not change significantly from baseline to ketamine in any region, thereby confirming previous literature with other NMDA receptor antagonists in rodents. Hence, in rats, we could not reproduce the findings in a human setup showing significant decreases in the [11C]ABP688 binding after a ketamine bolus followed by ketamine infusion. Species differences may have contributed to the different findings in the present study of rats. In conclusion, we could not confirm in rats that endogenous glutamate increases by ketamine infusion are reflected in [11C]ABP688 binding decreases as was previously shown for humans.

scholarly journals in vivo Variation in Metabotropic Glutamate Receptor Subtype 5 Binding Using Positron Emission Tomography and [11C]ABP688

2011 ◽  
Vol 31 (11) ◽  
pp. 2169-2180 ◽  
Author(s):  
Christine DeLorenzo ◽  
J S Dileep Kumar ◽  
J John Mann ◽  
Ramin V Parsey
Keyword(s):  
Positron Emission Tomography ◽  
Glutamate Receptor ◽  
Metabotropic Glutamate Receptor ◽  
Preliminary Evidence ◽  
Emission Tomography ◽  
Receptor Subtype ◽  
Metabotropic Glutamate ◽  
Pet Tracer ◽  
Positron Emission

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders. Recently, a positron emission tomography (PET) tracer exhibiting high selectivity and specificity for mGluR5, 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime ([11C]ABP688), was developed. In this work, eight healthy adult male humans were imaged twice to assess within-subject [11C]ABP688 binding variability using PET. In seven of the eight subjects, significantly higher binding was observed during the second (retest) scan. This binding increase could not be definitively explained by differences in ligand injected mass or dose, or changes in metabolism between scans. In addition, this type of systematic binding increase was not observed in a [11C]ABP688 test–retest study performed by our group on anaesthetized baboons. It is therefore possible that the increased binding was because of physiological changes occurring between scans, such as changes in endogenous glutamate levels. If PET imaging with [11C]ABP688 could detect such differences, as preliminary evidence suggests, it could be used to help uncover the role of glutamate in the pathophysiology of brain disorders. However, regardless of its ability to detect endogenous glutamate differences, [11C]ABP688 binding variability could make accurate assessments of drug occupancy or group differences using this ligand difficult.

scholarly journals mGluR5 binding changes during a mismatch negativity task in a multimodal protocol with [11C]ABP688 PET/MR-EEG

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Cláudia Régio Brambilla ◽  
Tanja Veselinović ◽  
Ravichandran Rajkumar ◽  
Jörg Mauler ◽  
Andreas Matusch ◽  
...  
Keyword(s):  
Mismatch Negativity ◽  
Metabotropic Glutamate Receptor ◽  
Posterior Cingulate Cortex ◽  
Functional Network ◽  
Binding Potential ◽  
Glutamatergic Neurotransmission ◽  
Allosteric Site ◽  
Metabotropic Glutamate ◽  
Functional Regions ◽  
Positron Emission

AbstractCurrently, the metabotropic glutamate receptor 5 (mGluR5) is the subject of several lines of research in the context of neurology and is of high interest as a target for positron-emission tomography (PET). Here, we assessed the feasibility of using [11C]ABP688, a specific antagonist radiotracer for an allosteric site on the mGluR5, to evaluate changes in glutamatergic neurotransmission through a mismatch-negativity (MMN) task as a part of a simultaneous and synchronized multimodal PET/MR-EEG study. We analyzed the effect of MMN by comparing the changes in nondisplaceable binding potential (BPND) prior to (baseline) and during the task in 17 healthy subjects by applying a bolus/infusion protocol. Anatomical and functional regions were analyzed. A small change in BPND was observed in anatomical regions (posterior cingulate cortex and thalamus) and in a functional network (precuneus) after the start of the task. The effect size was quantified using Kendall’s W value and was 0.3. The motor cortex was used as a control region for the task and did not show any significant BPND changes. There was a significant ΔBPND between acquisition conditions. On average, the reductions in binding across the regions were - 8.6 ± 3.2% in anatomical and - 6.4 ± 0.5% in the functional network (p ≤ 0.001). Correlations between ΔBPND and EEG latency for both anatomical (p = 0.008) and functional (p = 0.022) regions were found. Exploratory analyses suggest that the MMN task played a role in the glutamatergic neurotransmission, and mGluR5 may be indirectly modulated by these changes.

Sign in / Sign up

Export Citation Format

Share Document