title: 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.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan, yamato@nirs.go.jp.
authors.forename: Tomoteru
authors.initials: T
authors.lastname: Yamasaki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujinaga
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan, SHI Accelerator Service, Tokyo 141-8686, Japan, and.
authors.forename: Kenji
authors.initials: K
authors.lastname: Furutsuka
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan, SHI Accelerator Service, Tokyo 141-8686, Japan, and.
authors.forename: Nobuki
authors.initials: N
authors.lastname: Nengaki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shimoda
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan, Tokyo Nuclear Services, Tokyo 110-0016, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shiomi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takei
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Yui
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Hidekatsu
authors.identifier: http://orcid.org/0000-0002-1101-4315
authors.initials: H
authors.lastname: Wakizaka
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Hatori
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Lin
authors.initials: L
authors.lastname: Xie
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Kumata
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D018683:Excitatory Amino Acid Agents / Q000493:pharmacokinetics; D005106:Exploratory Behavior / Q000502:physiology; D005260:Female; D006801:Humans; D009043:Motor Activity / Q000235:genetics; D010091:Oximes; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines; D011868:Radioisotopes / Q000493:pharmacokinetics / Q000494:pharmacology; D011877:Radionuclide Imaging; D051381:Rats; D055647:Rats, Transgenic; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D013912:Threonine / Q000235:genetics; D013997:Time Factors; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; D018683:Excitatory Amino Acid Agents; D010091:Oximes; D011725:Pyridines; D011868:Radioisotopes; D018094:Receptors, Metabotropic Glutamate; D051844:alpha-Synuclein; C104077:metabotropic glutamate receptor type 1; D013912:Threonine; D000409:Alanine
keywords: PET; Parkinson's disease; dopamine transporter; mGluR1; mGluR5; nondisplaceable binding potential