Cerebellum and cerebellar-regulated circuit contribution to Fragile X Syndrome

项目摘要 没有针对性治疗自闭症谱系障碍（ASD），作为潜在的机制， 仍然知之甚少。最近的研究暗示小脑在ASD的发病机制中，我们有 最近表明，小脑功能障碍足以产生ASD相关行为。但 小脑功能障碍对脆性X综合征（FXS）中这些行为的贡献尚不清楚。 FXS是ASD最重要的单基因病因，小脑功能障碍与ASD的发生有关。 ASD和FXS的发病机制。之前的研究已经证明了Fmr 1在免疫系统中的重要作用 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然未知。在这份提案中，我们假设， 目前的初步数据支持小脑Fmr 1功能障碍足以产生ASD行为， 包括社交功能障碍和感官超敏反应为了评估这一假设，我们在目标1中提出， 建立浦肯野细胞Fmr 1在ASD相关行为调节中的作用，并进一步评估 小脑Fmr 1缺失后，电生理和分子机制被破坏。 有证据表明，小脑功能障碍有助于ASD行为，我们也假设， 产生的初步数据支持特定的小脑小叶CrusI参与ASD相关行为 以及这个小叶和顶叶联合皮质之间的回路连接，顶叶联合皮质是一个与ASD有关的区域， 在感官处理中。在Aim 2中，我们将描述右侧CrusI -顶叶联合皮层的参与 ASD相关行为中的电路，并研究电路调制对ASD相关行为的影响 和小脑FXS小鼠模型中的皮质过度兴奋性。 最后，我们也提出假设，并显示初步的数据，以支持小脑功能正常化 本身可能足以改善FXS的整体（全身敲除）模型中的ASD相关行为。 在Aim 3中，我们将描述在小脑中特异性重新引入Fmr 1的益处， FMR 1突变小鼠。此外，我们将进一步评估小脑的潜在益处。 在这个整体Fmr 1突变小鼠模型中，神经调节对行为和皮质过度兴奋性的影响。 综上所述，在这个建议中，我们将建立Fmr 1在小脑中的作用，并建立其在小脑中的作用。 与自闭症相关的行为。我们还将研究驱动这些的分子机制， 的贡献，并研究在小脑内重新引入Fmr 1的好处，否则全球 Fmr 1突变体。最后，我们将研究小脑神经调节对ASD相关行为的益处， 小脑和整体FXS小鼠模型。因此，这些研究不仅将进一步加深我们对基础的理解， FXS中ASD相关行为的分子和电路机制，但也将揭示潜在的电路 和治疗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.