Transmitter release in a model of hyperactivity

描述(由申请人提供)：病理性多动在几种神经系统疾病中被观察到，包括注意力缺陷多动障碍(ADHD)和抽动症(TS)。这项研究的总体目标是通过使用定义明确的动物模型来识别最终导致多动临床表现的异常细胞事件，以了解病理性多动的病因。我们已经确定小鼠突变缺陷症是一种新的多动症动物模型。这些小鼠极度活跃，其运动活动量超过对照小鼠的3倍。我们已经证明，假瘤小鼠表达的过度活跃显然是Snap基因缺失的结果。该基因编码SNAP-25，这是一种神经元特异性蛋白，是在突触前膜停靠和保持突触小泡以准备迎接钙离子触发的神经递质胞吐所必需的机械组件。尽管SNAP-25在所有神经元中都有表达，但我们的实验主要集中在儿茶酚胺(Dys)的调节上，因为儿茶酚胺已知可以调节人和动物的多动。我们发现儿茶酚胺调节的缺陷是纹状体和伏隔核特有的；去甲肾上腺素(NE)浓度显著增加，而多巴胺(DA)利用率降低。NE和DA的调节在所有其他大脑区域都是正常的。NE的增加可能与这些小鼠运动性多动的表达有关，因为NE的耗竭改善了缺陷性小鼠的多动。这些结果为这种病理状态下去甲肾上腺素可能调节运动多动的假说提供了有力的证据。在这个小鼠模型中NE的异常调节尤其相关，因为已经在ADHD和TS中发现了NE的异常。

DESCRIPTION (provided by applicant): Pathologic hyperactivity is observed in several neurologic disorders including Attention Deficit Hyperactivity Disorder (ADHD) and Tourette's syndrome (TS). The general goal of this research is to understand the etiology of pathologic hyperactivity by using a well-defined animal model to identify abnormal cellular events that ultimately result in the clinical manifestation of hyperactivity. We have identified the mouse mutant coloboma as a novel animal model of hyperactivity. These mice are profoundly hyperactive with locomotor activity exceeding 3 times that of their control littermates. We have demonstrated that the hyperactivity expressed by coloboma mice is clearly the result of a deletion of the Snap gene. This gene encodes SNAP-25, a neuron-specific protein that is a component of the machinery essential for docking and holding synaptic vesicles at the presynaptic membrane in readiness for Ca 2+ triggered neurotransmitter exocytosis. Although SNAP-25 is expressed in all neurons, our experiments have focused on catecholamine (dys) regulation because catecholamines are known to regulate hyperactivity in both man and animals. We have found that defects in catecholamine regulation are specific to the striatum and nucleus accumbens; norepinephrine (NE) concentrations are significantly increased while dopamine (DA) utilization is decreased. NE and DA regulation is normal in all other brain regions. The increase in NE likely contributes to the expression of locomotor hyperactivity in these mice as depletion of NE ameliorates the coloboma mouse hyperactivity. These results provide strong evidence for the hypothesis that, in this pathologic state, NE may modulate locomotor hyperactivity. The aberrant regulation of NE in this mouse model is especially relevant, as abnormalities in NE have been identified in ADHD and TS.