SNAP-25 EXPRESSION AND HYPERACTIVITY IN COLOBOMA MICE

神经突触特定模式的建立和调控 连通性对正常的大脑功能至关重要。而且，很可能， 突触形成的异常可能会导致神经学和 精神障碍。这项研究计划的总体目标是 为了实现对基础的分子机制的理解 对参与这一过程的基因进行调控。的直接目标是 拟议的调查是为了评估SNAP-25的参与情况， 进化高度保守的突触前神经末梢蛋白，在 小鼠神经学表现出的自发性多动障碍 突变假单胞菌Cm.据认为，小鼠的CM突变可能是 包含Snap-25基因的缺失提供了一个值得关注的模型 儿童缺陷多动障碍(ADHD) 为了实现这些目标，cm突变的基因组结构和范围 将通过分析限制性片段长度多态来定义 (RFLP)的种间杂交种。探头 与已知邻近Snap-25基因座的基因和来自酵母的探针 人工染色体(YAC)文库将用于识别哪些 特定的序列被删除，从而映射CM的边界 删除。第二个具体目标是充分描述多动症患者的特征。 心理刺激剂对Cm/+突变小鼠运动行为的影响 毒品。这些研究将揭示多巴胺能系统是否参与 并以与注意缺陷多动症相似的方式做出反应。第三个目标是 试图通过修复缺陷型小鼠的行为缺陷 通过获得过表达该基因的转基因动物和 与突变菌株杂交。最终目标是评估 Snap-25基因直接表达在多动和行为中的作用 通过靶向基因破坏来明确地取消其表达 并重新融入转基因动物的种系。 通过这些研究，我们期待着一种新的、有用的ADHD模型 将被建立，并且SNAP-25或其他 参与多动障碍发展的因素将是 已确认身份。

The establishment and modulation of specific patterns of neural synaptic connectivity is crucial to normal brain function. It is likely, moreover, that abnormalities in synapse formation may, contribute to neurologic and psychiatric disorders. The overall objective of this research program is to achieve an understanding of the molecular mechanisms which underlie the regulation of genes that contribute to this process. The direct aims of the proposed investigation are to evaluate the involvement of SNAP-25, a highly evolutionary conserved presynaptic nerve terminal protein, in the spontaneous hyperactivity disorder exhibited by the mouse neurological mutant Coloboma, Cm. It is proposed that the Cm mutation in mice that encompasses a deletion of the Snap-25 gene provides a model for Attention Deficit Hyperactivity Disorder (ADHD) of children. To achieve these goals, the genomic structure and scope of the Cm mutation will be defined by analysis of restriction fragment length polymorphisms (RFLPS) of interspecies hybrids between Coloboma and Mus spretus. Probes to genes known to neighbor the Snap-25 locus and probes derived from yeast artificial chromosome (YAC) libraries will be used to identify which specific sequences are deleted and thereby map the boundaries of the Cm deletion. The second specific aim is to characterize fully the hyperactive locomotor behavior of Cm/+ mutant mice in response to psychostimulant drugs. These studies will reveal whether dopaminergic systems are involved and respond in a manner similar to that observed in ADHD. The third aim is to attempt to rescue the behavioral deficits of Coloboma mice through complementation by deriving transgenic animals overexpressing the gene and crossbreeding with the mutant strain. The final aim is to evaluate the function of Snap-25 gene expression directly in hyperactivity and behavior by specifically abolishing its expression through targeted gene disruption and reintegration into the germline of transgenic animals. Through these studies, we anticipate that a new and useful model of ADHD will be established and the possible contribution of SNAP-25 or additional factors involved in the development of hyperactivity disorders will be identified.