Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome

项目摘要 目前还没有针对自闭症谱系障碍(ASD)的靶向治疗方法，作为其潜在机制 人们对此仍然知之甚少。最近的研究表明小脑与ASD的发病机制有关，我们已经 最近研究表明，小脑功能障碍足以产生与ASD相关的行为。然而， 小脑功能障碍对脆性X综合征(FXS)这些行为的影响尚不清楚。 FXS是ASD最重要的单基因原因，小脑功能障碍与 ASD和FXS的发病机制。以前的研究已经证明Fmr1在血管生成中的重要作用。 小脑--从树突形态到突触可塑性；然而，小脑的贡献 FXS中自闭症相关行为的功能障碍仍不清楚。在这个提案中，我们假设和 提供初步数据支持小脑Fmr1功能障碍足以产生ASD行为， 包括社交功能障碍和感觉过敏。为了评估这一假设，我们在Aim1中建议 建立浦肯野细胞Fmr1在调节ASD相关行为中的作用并进一步评估 当小脑Fmr1丢失时，电生理和分子机制被破坏。 根据小脑功能障碍导致ASD行为的证据，我们还假设和 生成的初步数据支持特定的小脑小叶Crusi参与ASD相关行为 以及该小叶和顶叶联合皮质之间的电路连接，该区域与ASD和 在感官处理方面。在AIM2中，我们将描述右侧十字顶叶联合皮质的受累情况 ASD相关行为中的电路，并调查电路调制对ASD相关行为的影响 以及小脑FXS小鼠模型中的皮质高兴奋性。 最后，我们还假设并展示了支持小脑功能正常化初步数据 在FXS的全球(全身敲除)模型中，其本身可能足以改善ASD相关行为。 在Aim3中，我们将描述将Fmr1特异性地重新引入小脑的好处 全球Fmr1突变小鼠。此外，我们还将进一步评估小脑的潜在益处。 这一全球Fmr1突变小鼠模型中的神经调节对行为和皮质超兴奋性的影响。 综上所述，在这项提案中，我们将确定Fmr1在小脑中的角色，并建立其 对自闭症相关行为的贡献。我们还将研究驱动这些变化的分子机制。 并检查在小脑内重新引入Fmr1的好处，否则将 FMR1突变体。最后，我们将研究小脑神经调节对自闭症相关行为的益处。 小脑和全球FXS小鼠模型。因此，这些研究不仅将加深我们对基本知识的理解 FXS中ASD相关行为的分子和电路机制，但也将阐明潜在的电路 以及治疗FXS的分子靶点。

Project Summary No targeted therapies exist for treatment of Autism Spectrum Disorders (ASD), as the underlying mechanisms remain poorly understood. Recent studies implicate the cerebellum in the pathogenesis of ASD, and we have recently shown that cerebellar dysfunction is sufficient to generate ASD-relevant behaviors. However, the contribution of cerebellar dysfunction to these behaviors in Fragile X Syndrome (FXS) is unknown. FXS is the most significant monogenic cause of ASD, and cerebellar dysfunction has been implicated in the pathogenesis of both ASD and FXS. Previous studies have demonstrated important roles for Fmr1 in the cerebellum – from dendritic morphology to synaptic plasticity; however, the contribution of cerebellar dysfunction to autism-relevant behaviors in FXS remains unknown. In this proposal, we hypothesize and present preliminary data to support that cerebellar Fmr1 dysfunction is sufficient to generate ASD behaviors, including social dysfunction and sensory hypersensitivity. To evaluate this hypothesis, we propose in Aim1 to establish the role for Purkinje cell Fmr1 in the regulation of ASD-relevant behaviors and to further evaluate electrophysiological and molecular mechanisms that are disrupted upon loss of cerebellar Fmr1. With evidence that cerebellar dysfunction contributes to ASD behaviors, we also hypothesized and have generated preliminary data to support specific cerebellar lobule CrusI involvement in ASD-related behaviors and circuit connections between this lobule and the parietal association cortex, a region implicated in ASD and in sensory processing. In Aim2, we will delineate the involvement of right CrusI – parietal association cortex circuits in ASD-relevant behaviors and investigate the impact of circuit modulation on ASD-relevant behaviors and cortical hyper-excitability in the cerebellar FXS mouse model. Lastly, we also hypothesize and show preliminary data to support that normalization of cerebellar function might itself be sufficient to ameliorate ASD-related behaviors in a global (whole body knockout) model of FXS. In Aim3, we will delineate the benefit of reintroduction of Fmr1 specifically into the cerebellum in an otherwise global Fmr1 mutant mouse. In addition, we will further evaluate the potential benefit of cerebellar neuromodulation in this global Fmr1 mutant mouse model on behavior and cortical hyper-excitability. Taken together, in this proposal, we will establish the roles for Fmr1 in the cerebellum and establish its contribution to autism-related behaviors. We will additionally examine the molecular mechanisms driving these contributions and examine the benefits of reintroduction of Fmr1 within the cerebellum in an otherwise global Fmr1 mutant. Lastly, we will examine the benefit of cerebellar neuromodulation on ASD-relevant behaviors in cerebellar and global FXS mouse models. Thus, these studies will not only further our understanding of basic molecular and circuit mechanisms of ASD-relevant behaviors in FXS but will also shed light on potential circuit and molecular targets for therapy for FXS.