Serotonin 5-HT4 Receptor Agonists Improve Facilitation of Contextual Fear Extinction in an MPTP-Induced Mouse Model of Parkinson's Disease
Serotonin 5-HT4 Receptor Agonists Improve Facilitation of Contextual Fear Extinction in an MPTP-Induced Mouse Model of Parkinson's Disease
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DOI：
10.3390/ijms20215340
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Muroi, Yoshikage
中科院分区：
文献类型：
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作者：
Ishii, Toshiaki;Kinoshita, Ken-ichi;Muroi, Yoshikage
在此之前，我们发现1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的帕金森病（PD）模型小鼠（PD mice）表现出通过减少环磷酸腺苷（cAMP）/cAMP依赖性反应元件结合蛋白（CREB）信号而促进海马记忆消退，这可能导致PD的认知障碍。中缝中核（MnRN）中的5-羟色胺能神经元投射到海马，并且已经报道了功能异常。在本研究中，我们研究了5-羟色胺5-HT 4受体（5-HT 4 R）激动剂普卢卡必利和维舒曲对PD小鼠记忆消退的促进作用。这两种5-HT 4 R激动剂通过刺激海马齿状回中的cAMP/CREB通路恢复了PD小鼠中情境恐惧消退的促进作用。逆行荧光金示踪剂研究显示，黑质网状部分（SNr）中的γ-氨基丁酸能（GABA能）神经元（而非黑质腹侧部（SNpc）中的多巴胺能（DA能）神经元）投射到MnRN中的多巴胺能神经元，已知MnRN将其神经末梢投射到海马。PD小鼠中SNpc DA能神经元的变性可能影响SNr GABA能神经元，然后影响MnRN中的DA能神经元，导致海马功能障碍。这些发现表明，5-HT 4受体激动剂可能是潜在的有用的治疗药物，用于治疗认知功能障碍的PD。
Previously, we found that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) model mice (PD mice) showed facilitation of hippocampal memory extinction via reduced cyclic adenosine monophosphate (cAMP)/cAMP-dependent response element-binding protein (CREB) signaling, which may cause cognitive impairment in PD. Serotonergic neurons in the median raphe nucleus (MnRN) project to the hippocampus, and functional abnormalities have been reported. In the present study, we investigated the effects of the serotonin 5-HT4 receptor (5-HT4R) agonists prucalopride and velusetrag on the facilitation of memory extinction observed in PD mice. Both 5-HT4R agonists restored facilitation of contextual fear extinction in PD mice by stimulating the cAMP/CREB pathway in the dentate gyrus of the hippocampus. A retrograde fluorogold-tracer study showed that gamma -aminobutyric acid-ergic (GABAergic) neurons in the reticular part of the substantia nigra (SNr), but not dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc), projected to serotonergic neurons in the MnRN, which are known to project their nerve terminals to the hippocampus. It is possible that the degeneration of the SNpc DAergic neurons in PD mice affects the SNr GABAergic neurons, and thereafter, the serotonergic neurons in the MnRN, resulting in hippocampal dysfunction. These findings suggest that 5HT4R agonists could be potentially useful as therapeutic drugs for treating cognitive deficits in PD.