Journal Article Dynamic Changes in Striatal mGluR1 but not mGluR5 During Pathological Progression of Parkinson’ s Disease in Human Alpha-Synuclein A53T Transgenic Rats:A Multi-PET Imaging Study

Yamasaki, Tomoteru  ,  Fujinaga, Masayuki  ,  Kawamura, Kazunori  ,  Furutsuka, Kenji  ,  Nengaki, Nobuki  ,  Shimoda, Yoko  ,  Shiomi, Satoshi  ,  Takei, Makoto  ,  Hashimoto, Hiroki  ,  Yui, Joji  ,  Wakizaka, Hidekatsu  ,  Hatori, Akiko  ,  Xie, Lin  ,  Kumata, Katsushi  ,  Ming-Rong, Zhang

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 [11C]ITDM (N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[11C]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)-[11C]ABP688 [3-(6-methylpyridin-2-ylethynyl)-cyclohex-2-enone-(E)-O-[11C]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 [18F]FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2β-carbo-[18F]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.

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