Cortico-striatal synaptic defects and compulsive motor behaviors in mice

描述(申请人提供)：动物模型是研究人类疾病机制和测试新疗法的重要工具。我们已经在小鼠中发现了一种强迫性梳理障碍，这种障碍发生在突触后密度(PSD)的一个关键支架成分缺失之后。小鼠这种行为的发病机制可能与人类强迫症(OCD)样焦虑症的障碍有关。这个小鼠模型现在为我们提供了一个从基因到突触功能再到回路到行为的发病机制研究的机会。拟议的实验将通过描绘这种PSD成分的丧失如何改变突触后组成、突触传递和皮质-纹状体回路来开始建立这些联系。我们进一步提出了救援性实验，以恢复皮质-纹状体突触的突触功能，并最终确定足以恢复动物正常行为的关键回路。综上所述，这些实验结果将促进我们对皮质纹状体突触的突触后组装和突触传递的理解。这些基础对人类未来直接治疗强迫症样障碍和其他由异常基底节突触传递引起的实体至关重要。

DESCRIPTION (provided by applicant): Animal models are an important tool for studying human disease mechanisms and testing new therapies. We have identified a compulsive grooming disorder in mice following deletion of a key scaffolding component of the post-synaptic density (PSD). The pathogenesis of this behavior in mice may relate to disorders in the Obsessive Compulsive Disorder (OCD)-like spectrum of anxiety disorders in humans. This mouse model now affords us an opportunity to study pathogenesis from gene to synaptic function to circuit to behavior. The experiments proposed will begin to establish these links by delineating how the loss of this PSD component alters post-synaptic composition, synaptic transmission, and cortico-striatal circuitry. We further propose rescue experiments to restore synaptic function at cortico-striatal synapses and eventually to determine the critical circuitry sufficient to restore normal behavior to the animal. In sum, the results of these experiments will advance our understanding of post-synaptic assembly and synaptic transmission at cortico- striatal synapses. These underpinnings are critical to direct future therapies in humans for OCD-like disorders and other entities arising from abnormal basal ganglia synaptic transmission.