Elucidation of synaptic changes in parkinsonism using novel PARK15 mouse models

人类PARK15(Fbxo7)基因突变与帕金森锥体综合征有关，帕金森综合征是帕金森综合征的一种青少年形式。虽然Fbxo7基因的缺失不会导致小鼠神经元的退化，但当前脑的谷氨酸能神经元被切除时，它会引发早发性运动障碍，而当多巴胺能神经元的基因缺失时，它会引发进行性的、迟发性的运动缺陷。纹状体突触的关键调节剂多巴胺水平和纹状体关键突触蛋白水平的变化有力地支持了突触完整性和基本运动回路经历了重大变化并导致运动缺陷的观点。由于帕金森氏症在疾病的早期阶段被视为一种突触疾病，因此这些观察结果尤其重要。本研究方案的目标如下：1.小鼠谷氨酸能神经元中Fbxo7的缺失对其神经传递产生负面影响，导致纹状体中多巴胺的增加。小鼠的表型使人联想到PARK15患者的锥体体征和PD患者的左旋多巴引发的运动障碍。在分子水平上，我们发现这些小鼠的纹状体内吞和胞吐途径以及突触消除途径都发生了变化。此外，我们还在海马区发现了一种显著的电生理表型。因此，我们的初步数据促使我们对前脑网络的分子和电生理变化进行更详细的研究。从多巴胺能神经元中删除Fbxo7会触发小鼠纹状体中的慢性多巴胺缺乏，这让人想起帕金森病患者中多巴胺水平的下降。纹状体突触的适当调节不再有效。因此，我们假设作为多巴胺能输入受损的结果，谷氨酸能突触也经历了适应。因此，我们将特别关注突触在数量水平上的分子变化，但我们也将监测这些小鼠纹状体的电生理变化。

Mutations in the human PARK15 (FBXO7) gene have been implicated in Parkinsonian pyramidal syndrome, a juvenile form of parkinsonism. While deletion of the Fbxo7 gene does not result in the degeneration of neurons in mice, it triggers early-onset motor deficits when ablated from glutamatergic neurons of the forebrain and progressive, late-onset motor defects when deleted in dopaminergic neurons. Alterations in the level of dopamine, a critical modulator of the striatal synapse and in the levels of key synaptic proteins in the striatum strongly support the notion that synaptic integrity and essential motor circuits underwent significant changes and are causative for the motor defects. Since parkinsonism is viewed as a synaptopathy in the early stages of the disease, these observations are particularly important. The goals of this research proposal are as follows:1. The loss of FBXO7 in glutamatergic neurons in mice negatively affects their neurotransmission, causing an increase in dopamine in the striatum. The phenotype of the mice is reminiscent of pyramidal signs in PARK15 patients and of levodopa-triggered dyskinesia in PD patients. At the molecular level, we found changes in endocytosis and exocytosis pathways, and in a synapse-elimination pathway in the striatum of these mice. In addition, we discovered a striking electrophysiological phenotype in the hippocampus. Hence, our preliminary data prompt a more detailed investigation of the molecular and electrophysiological changes of the networks in forebrain.2. The deletion of Fbxo7 from the dopaminergic neurons triggers a chronic dopamine deficit in the striatum in mice, which is reminiscent of the decreasing levels of dopamine in PD patients. The proper modulation of the striatal synapse is no longer effective. As a consequence, we hypothesize that as a result of the compromised dopaminergic input, the glutamatergic synapse undergoes adaptations as well. Hence, we will focus in particular on the molecular changes at the synapses at the quantitative level but we will also monitor the electrophysiological changes in the striatum of these mice.