The effect of PD-linked LRRK2 mutations on corticostriatal circuits

 描述（由申请人提供）：编码富含亮氨酸重复序列激酶2（LRRK2）的基因突变是帕金森病（PD）遗传形式的最常见原因，帕金森病是一种进行性神经退行性疾病，无法治愈。虽然对LRRK2的正常功能知之甚少，但遗传性PD的进展与特发性病例相同，这表明存在常见的疾病机制，并强调需要了解突变型LRRK2作用的致病机制和回路。LRRK2在背侧纹状体中富集，背侧纹状体是在PD中退化的多巴胺能神经元的主要靶点，但矛盾的是，其表达在突触发生期间发育达到峰值。这提出了一个难题，在一个领域，通常集中在后期的运动症状，并强调了解是否PD相关的突变LRRK2改变纹状体网络结构和功能的重要性。因此，我的目标是确定如何正常LRRK2和PD相关的突变形式的LRRK2控制兴奋性纹状体突触网络的发展。我将使用小鼠Lrrk2基因敲入模型和一套完整的电生理学，成像，解剖学和药物遗传学测定来表征发育过程中神经回路的改变。我推测PD相关的LRRK2突变形式导致皮质纹状体神经网络发育异常。我的初步数据强烈支持这一观点，因为表达PD患者中最常见的LRRK2突变的小鼠表现出显著改变的纹状体突触网络特性， 脊椎形态学早期的生活。此外，我希望能够确定这种异常活动的来源，因为我有初步的数据表明异常的纹状体输入来自皮质来源，以及异常的纹状体输入的影响如何影响下游基底神经节回路。该项目将揭示早期电路异常，可能是PD后期神经退行性变的基础。

 DESCRIPTION (provided by applicant): Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common cause of heritable forms of Parkinson's disease (PD), a progressive neurodegenerative disorder for which there is no cure. Though little is known about the normal function of LRRK2, inherited PD progresses identically to idiopathic cases, suggesting the existence of common disease mechanisms and highlighting the need to understand pathogenic mechanisms and circuits through which mutant LRRK2 acts. LRRK2 is enriched in dorsal striatum, the principal target of dopaminergic neurons that degenerate in PD, but paradoxically, its expression peaks developmentally during synaptogenesis. This has presented a conundrum in a field customarily focused on late-stage motor symptoms and underscores the importance of understanding whether PD-related mutations in LRRK2 alter striatal network structure and function early on. Accordingly, my objective is to determine how normal LRRK2 and a PD-related mutant form of LRRK2 control development of excitatory striatal synaptic networks. I will accomplish this using a mouse Lrrk2 knock-in model and with an integrated set of electrophysiological, imaging, anatomical, and pharmacogenetic assays to characterize alterations in neural circuits during development. I hypothesize that a PD-related mutant form of LRRK2 results in abnormal corticostriatal neural network development. My preliminary data strongly support this idea, as mice expressing the most common LRRK2 mutation seen in PD patients exhibit significantly altered striatal synaptic network properties and spine morphology early in life. Furthermore, I hope to identify both the source of this aberrant activity, as I have preliminary data that suggest aberrant striatal inputs arise from cortical sources, as well as how the effects of aberrant striatal inputs may effect downstream basal ganglia circuitry. This project will shed light on early circuit abnormalities that may underlie neurodegeneration in PD later in life.