Prefrontal AMPA receptors in FTD Pathogenesis

 描述（由申请方提供）：额颞叶痴呆（FTD）是一种与前额叶和前颞叶皮质局灶性萎缩相关的致死性疾病。FTD是65岁以下痴呆症的第二大常见原因（仅次于阿尔茨海默病），并且无法治愈。与其他主要的神经退行性疾病相比，很少有人知道它的分子，突触和电路水平的致病基础。以人格和社会行为的显著变化为特征的行为异常是FTD的标志。多达50%的FTD患者有该疾病的家族史，表明有很强的遗传成分。最近的分子遗传学研究已经确定了许多导致FTD的基因，包括CHMP 2B，前颗粒蛋白（GRN）和C9 ORF 72，为深入研究该疾病的致病机制铺平了道路。有趣的是，携带不同突变的FTD患者的临床结果往往惊人地相似，这表明相同的神经回路受到影响。为了在动物中建立FTD模型并阐明其潜在机制，我们制备了一种条件性转基因小鼠品系，该品系在前脑中表达导致FTD的CHMP 2BIntron 5。突变小鼠概括了FTD相关神经变性表型的几个关键特征，包括社会行为障碍。我们的研究揭示了AMPA受体（AMPAR）组成的显着变化，导致异常插入的Ca 2+不渗透AMPAR的内侧前额叶皮层（PFC）的突触。这种AMPAR失调似乎是由大脑富集的非编码microRNA miR-124的丢失驱动的。重要的是，在行为变体FTD（bvFTD）患者亚组的额叶皮质和iPSC衍生皮质神经元中也观察到miR-124和AMPAR的相似变化。这表明miR-124和AMPAR失调不仅限于CHMP 2BIntron 5突变，可能是FTD更常见突变的更普遍致病机制。基于这些结果，我们提出了一种新的FTD发病机制：PFC回路中突触AMPAR组装和功能的改变强调了FTD的社会行为障碍。本申请的目的是测试和建立“FTD的AMPAR假设”。我们将研究关键的AMPAR机制，并在现有的内侧PFC中绘制受影响的电路。（GRN单倍不足）和两个新产生的（CHMP 2BIntron 5和C9 ORF 72 AAV转基因小鼠，G4 C2重复扩增）FTD小鼠模型（目的1），建立miR-124-AMPAR致病轴，并通过操纵该轴，尤其是CP-AMPAR，在体内恢复小鼠模型的社会性缺陷（目的2），最后，验证AMPAR假设并探索人类患者iPSC衍生的具有不同基因突变的皮质神经元的治疗策略（目的3）。我们将使用多学科方法结合体内基因操作，电生理学，小鼠行为和人类iPSC技术。我们的结果将为旨在开发基于AMPAR的FTD治疗策略的转化研究奠定基础。

 DESCRIPTION (provided by applicant): Frontotemporal dementia (FTD) is a fatal disease associated with focal atrophy of the prefrontal and anterior temporal cortex. FTD is the second most common cause of dementia under age 65 (after Alzheimer's disease), and there is no cure. Compared to other major neurodegenerative disorders, very little is known about its pathogenic basis at molecular, synaptic, and circuit levels. Behavioral abnormalities, characterized by marked changes in personality and social conduct are hallmarks of FTD. As many as 50% of FTD patients have a family history of the disease, suggesting a strong genetic component. Recent molecular genetic studies have identified a number of FTD-causing genes, including CHMP2B, progranulin (GRN), and C9ORF72, paving the way for in-depth investigation of pathogenic mechanisms of the disease. Interestingly, the clinical outcome in FTD patients carrying different mutations is often strikingly similar, suggesting that the same neural circuits are affected. In an effort to model FTD in animals and elucidate underlying mechanisms, we have generated a conditional transgenic mouse strain that expresses an FTD-causing CHMP2BIntron5 in the forebrain. Mutant mice recapitulate several key features of FTD-associated neurodegeneration phenotypes, including social behavioral impairments. Our studies uncover a marked change in AMPA receptor (AMPAR) composition, leading to abnormal insertion of Ca2+-impermeable AMPARs in synapses of the medial prefrontal cortex (PFC). This AMPAR dysregulation appears to be driven by a loss of the brain-enriched noncoding microRNA miR-124. Importantly, similar changes in miR-124 and AMPARs are also observed in the frontal cortex and iPSC-derived cortical neurons from a subset of patients with behavioral variant FTD (bvFTD). This suggests that miR-124 and AMPAR dysregulation are not limited to CHMP2BIntron5 mutation, and are perhaps a more general pathogenic mechanism for FTD with more common mutations. Based on these results, we propose a novel mechanism of FTD pathogenesis: altered synaptic AMPAR assembly and function in PFC circuits underline the social behavioral impairments in FTD. The goal of this application is to test and establish this "AMPAR hypothesis of FTD". We will examine key AMPAR mechanisms and map affected circuits in the medial PFC in an existing (GRN haploinsufficiency) and two newly generated (CHMP2BIntron5 and C9ORF72 AAV transgenic mice with G4C2 repeat expansions) mouse models of FTD (Aim 1), establish the miR-124-AMPAR pathogenic axis and by manipulating this axis, especially CP-AMPARs, restore sociability deficits in mouse models in vivo (Aim 2), and finally, validate the AMPAR hypothesis and explore therapeutic strategies in human patient iPSC-derived cortical neurons harboring different genetic mutations (Aim 3). We will use a multidisciplinary approach combining in vivo gene manipulations, electrophysiology, mouse behavior, and human iPSC technologies. Our results will set the stage for translational studies aimed at developing an AMPAR-based therapeutic strategy for FTD.