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
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
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DOI：
10.1523/jneurosci.2289-15.2016
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发表时间：
2016-01-13
影响因子：
5.3
通讯作者：
Zhang, Ming-Rong
中科院分区：
文献类型：
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作者：
Yamasaki, Tomoteru;Fujinaga, Masayuki;Zhang, Ming-Rong
帕金森病 (PD) 是一种影响中枢神经系统的常见退行性疾病，其主要特征是静止性震颤和运动缺陷。 I 类代谢型谷氨酸受体亚型 1 和 5（分别为 mGluR1 和 mGluR5）是多种中枢神经系统疾病研究的重要靶点。在本研究中，我们通过对表达异常人α-突触核蛋白（ASN）基因的A53T转基因（A53T-Tg）大鼠进行纵向正电子发射断层扫描（PET）成像，研究了mGluR1和mGluR5在慢性PD病理学中的体内作用。 A53T-Tg 大鼠的一般运动活动随着年龄的增长而急剧下降，并伴有异常的 ASN 聚集和纹状体神经元变性。在纵向 PET 成像中，[C-11] ITDM（N-[4-[6-（异丙氨基）嘧啶-4-基]-1,3-噻唑-2-基]-N-甲基-4-[C-11]甲基苯甲酰胺）（mGluR1 的选择性 PET 配体）的纹状体不可置换结合电位 (BPND) 值在 PD 症状出现前暂时升高，随后随着年龄的增长而急剧下降。然而，(E)-[C-11]ABP688 [3-(6-甲基吡啶-2-乙炔基)-环己-2-烯酮-(E)-O-[C-11]甲基肟（mGluR5 的特定 PET 配体）的纹状体 BPND 值在实验期间保持恒定。纹状体 mGluR1 BPND 值的动态变化也显示出与一般运动活动的病理性下降高度相关。此外，mGluR1 BPND 值的下降与 [F-18[FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2 beta-carbo-[F-18]氟乙氧基-3 beta-(4-甲基苯基)去托烷] BPND 值的下降相关，[F-18[FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2 beta-carbo-[F-18]氟乙氧基-3 beta-(4-甲基苯基)去托烷]是多巴胺转运蛋白的特异性 PET 配体，多巴胺能神经元的生物标志物。总之，我们的结果首次证明，在 PD 动物模型中伴随病理进展的是 mGluR1 而不是 mGluR5 发生动态变化。
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 a-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 [C-11] ITDM (N-[4-[6-(isopropylamino) pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[C-11]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)-[C-11]ABP688 [3-(6-methylpyridin-2-ylethynyl)-cyclohex-2-enone-(E)-O-[C-11]methyloximel, 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 [F-18[FE-PE2I [(E)-N-(3-iodoprop-2E-enyl)-2 beta-carbo-[F-18]fluoroethoxy-3 beta-(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.