Parkinson's disease (PD) is a prevalent degenerative disorder affecting the CNS that is primarily characterized by
resting tremor and movement deficits. Group I
metabotropic glutamate receptor subtypes 1 and 5 (
mGluR1 and mGluR5, respectively) are important targets for investigation in several CNS disorders. In the present study, we investigated the in vivo roles of
mGluR1 and mGluR5 in chronic PD pathology by performing longitudinal positron emission tomography (PET) imaging in A53T transgenic (A53T-Tg) rats expressing an abnormal human α-
synuclein (ASN) gene. A53T-Tg rats showed a dramatic decline in general motor activities with age, along with abnormal ASN aggregation and striatal
neuron degeneration. In longitudinal PET imaging, striatal nondisplaceable binding potential (BPND) values for [(11)C]ITDM (N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[(11)C]methylbenzamide), a selective PET
ligand for
mGluR1, temporarily increased before PD symptom onset and dramatically decreased afterward with age. However, striatal BPND values for (E)-[(11)C]
ABP688 [3-(6-methylpyridin-2-ylethynyl)-cyclohex-2-enone-(E)-O-[(11)C]methyloxime], a specific PET
ligand for mGluR5, remained constant during experimental terms. The dynamic changes in striatal
mGluR1 BPND values also showed a high correlation in pathological decreases in general motor activities. Furthermore, declines in
mGluR1 BPND values were correlated with decreases in BPND values for [(18)F]FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2β-carbo-[(18)F]fluoroethoxy-3β-(4-methylphenyl) nortropane], a specific PET
ligand for the
dopamine transporter, a
biomarker for dopaminergic neurons. In conclusion, our results have demonstrated for the first time that dynamic changes occur in
mGluR1, but not mGluR5, that accompany pathological progression in a PD animal model.
SIGNIFICANCE STATEMENT: Synaptic signaling by
glutamate, the principal excitatory
neurotransmitter in the brain, is modulated by group I
metabotropic glutamate receptors, including the
mGluR1 and mGluR5 subtypes. In the brain,
mGluR1 and mGluR5 have distinct functional roles and regional distributions. Their roles in brain pathology, however, are not well characterized. Using longitudinal PET imaging in a chronic rat model of PD, we demonstrated that expression of
mGluR1, but not mGluR5, dynamically changed in the striatum accompanying pathological PD progression. These findings imply that monitoring
mGluR1 in vivo may provide beneficial information to further understand
central nervous system disorders.