Modulation of D2 and mGlu5 Receptor Function in Parkinson’s Disease: A PET and phMRI Study in Rats
Poster No:
115
Submission Type:
Abstract Submission
Authors:
Iris Chen1, Zeynep Saur2, Rajshree Ghosh Biswas2, Yang Sun3, Bruce Jenkins1, Anna-Liisa Brownell4
Institutions:
1Athinoula A. Martinos Center for Biomedical Imaging, MGH and Harvard Medical School, Charlestown, MA, 2Athinoula A. Martinos Center for Biomedical Imaging, MGH, Charlestown, MA, 3Center for Nuclear Medicine and Theranostic Sciences, MGH, Charlestown, MA, 4Center for Nuclear Medicine and Theranostic Sciences, MGH and Harvard Medical School, Charlestown, MA
First Author:
Iris Chen
Athinoula A. Martinos Center for Biomedical Imaging, MGH and Harvard Medical School
Charlestown, MA
Athinoula A. Martinos Center for Biomedical Imaging, MGH and Harvard Medical School
Charlestown, MA
Co-Author(s):
Bruce Jenkins
Athinoula A. Martinos Center for Biomedical Imaging, MGH and Harvard Medical School
Charlestown, MA
Athinoula A. Martinos Center for Biomedical Imaging, MGH and Harvard Medical School
Charlestown, MA
Anna-Liisa Brownell
Center for Nuclear Medicine and Theranostic Sciences, MGH and Harvard Medical School
Charlestown, MA
Center for Nuclear Medicine and Theranostic Sciences, MGH and Harvard Medical School
Charlestown, MA
Introduction:
Parkinson's disease (PD) symptoms, particularly motor deficits, arise from the loss of dopaminergic neurons in the substantia nigra, resulting in hyperactivity in the indirect pathway and hypoactivity in the direct pathway. This disruption of dopamine (DA) signaling dysregulates Group I metabotropic glutamate receptors (mGluR1 and mGluR5), exacerbating excitotoxic glutamate signaling and disrupting basal ganglia circuitry, thereby worsening motor symptoms. However, the interactions between dopamine receptors (DAR) and mGluR signaling during PD progression remain poorly understood. This study investigated the status and interaction of DAR and mGluR using simultaneous pharmacological MRI (phMRI) and PET imaging in a transgenic rat model of PD. We aimed to assess how DAR and mGluR functions change during disease progression and whether the influence of DA on mGluR, or vice versa, is modified as the disease advances. Our findings may inform drug development for disorders related to dopamine-glutamate regulation, including PD, schizophrenia, and drug addiction.
Methods:
The transgenic PD rats: A53T mutation on the α-synuclein human gene. This study involves a multi-year timeline for rats to develop PD symptoms. The PD rats analyzed here were in the pre-symptomatic stage without behavioral deficits.
phMRI: A general DA releaser, d-amphetamine (dAMPH), was used to increase synaptic DA levels, while the mGluR5 antagonist MTEP ((2-methyl-1,3-thiazo-4-yl)ethynyl pyridine) was used to perturb the mGluR signal. phMRI was acquired with a Bruker 4.7T scanner using a conventional gradient echo sequence (TR/TE 400 / 4 msec, FOV 32mm X 32 mm, dim 128X128, 29 slices (0.8mm), with 1.4 partial FT, temporal resolution is 30sec/time point), using feraheme to sensitize MR signal to relative cerebral blood volume (rCBV) changes.
PET: 18F-Fallypride was used to assess DA D2 receptor (D2R) binding, while 18F-FPEB was used to assess mGluR5 binding. To evaluate how DA signaling affects mGluR receptors, a cold AMPH challenge (1.5 mg/kg, IV) was administered 20 minutes after the 18F-FPEB injection. To investigate how mGluR signaling affects DA receptors, MTEP was given 15 minutes after the 18F-Fallypride injection. The PET insert, which fits into the BGA-20S-HP MRI gradient, provides a resolution of 0.7 mm, with Full Field Accuracy (FFA) and 12% sensitivity.
phMRI: A general DA releaser, d-amphetamine (dAMPH), was used to increase synaptic DA levels, while the mGluR5 antagonist MTEP ((2-methyl-1,3-thiazo-4-yl)ethynyl pyridine) was used to perturb the mGluR signal. phMRI was acquired with a Bruker 4.7T scanner using a conventional gradient echo sequence (TR/TE 400 / 4 msec, FOV 32mm X 32 mm, dim 128X128, 29 slices (0.8mm), with 1.4 partial FT, temporal resolution is 30sec/time point), using feraheme to sensitize MR signal to relative cerebral blood volume (rCBV) changes.
PET: 18F-Fallypride was used to assess DA D2 receptor (D2R) binding, while 18F-FPEB was used to assess mGluR5 binding. To evaluate how DA signaling affects mGluR receptors, a cold AMPH challenge (1.5 mg/kg, IV) was administered 20 minutes after the 18F-FPEB injection. To investigate how mGluR signaling affects DA receptors, MTEP was given 15 minutes after the 18F-Fallypride injection. The PET insert, which fits into the BGA-20S-HP MRI gradient, provides a resolution of 0.7 mm, with Full Field Accuracy (FFA) and 12% sensitivity.
Results:
The basal binding potential (BP) of mGluR5 (F18-FPEB) was significantly decreased in pre-symptomatic PD rats compared to normal control rats. These BP decreases were significant in both male and female groups. The challenge with dAMPH did not result in changes in mGluR5 BP in either PD or control rats. However, phMRI revealed that PD rats exhibited significantly higher rCBV increases in cortical motor/pre-motor areas compared to control rats.
The basal BP of D2R (F18-Fallypride) was similar between control and PD rats. Following the administration of the mGluR5 antagonist MTEP (2 mg/kg), D2R BP increased in the striatum of male PD rats but not in females or control rats. While there were no observed gender differences, phMRI with MTEP showed significant rCBV increases in the cortex but not in the striatum of PD rats. Sufficient data from control rats for comparison are not yet available.
The basal BP of D2R (F18-Fallypride) was similar between control and PD rats. Following the administration of the mGluR5 antagonist MTEP (2 mg/kg), D2R BP increased in the striatum of male PD rats but not in females or control rats. While there were no observed gender differences, phMRI with MTEP showed significant rCBV increases in the cortex but not in the striatum of PD rats. Sufficient data from control rats for comparison are not yet available.
Conclusions:
The simultaneous phMRI/PET studies demonstrate the potential to detect early pathological changes in vivo during the pre-symptomatic stage of Parkinson's disease. Ongoing longitudinal studies aim to reveal how basal D2R/mGluR5 binding potential (BP) changes as the disease progresses, as observed through PET imaging, and how D2/mGluR signaling modulates neuronal function via phMRI and the effects of delayed challenges in PET binding studies.
Supported by NIH R01NS124777 and 1S10OD026987, and 4.7T Bruker PET-MR by NIH SIG S10-OD034258
Supported by NIH R01NS124777 and 1S10OD026987, and 4.7T Bruker PET-MR by NIH SIG S10-OD034258
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Transmitter Receptors
Novel Imaging Acquisition Methods:
Multi-Modal Imaging
Physiology, Metabolism and Neurotransmission:
Pharmacology and Neurotransmission 2
Keywords:
Aging
ANIMAL STUDIES
Basal Ganglia
Degenerative Disease
Dopamine
Neurological
Neurotransmitter
Positron Emission Tomography (PET)
RECEPTORS
Other - CBV, phMRI, Parkinson's Disease, simultaneous PET-MRI
1|2Indicates the priority used for review