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，包括注意缺陷多动障碍（ADHD）和图雷特综合征（TS）。本研究的总体目标是通过使用定义良好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，从而了解病理性多动的病因。我们已经确定了小鼠突变结肠瘤作为一种新的动物模型多动症。这些小鼠极度活跃，运动活动超过对照组同伴的3倍。我们已经证明，结肠瘤小鼠表达的多动症显然是Snap基因缺失的结果。该基因编码SNAP-25， SNAP-25是一种神经元特异性蛋白，是突触前膜对接和保持突触囊泡为ca2 +触发的神经递质胞外分泌做好准备所必需的机制组成部分。尽管SNAP-25在所有神经元中表达，但我们的实验主要集中在儿茶酚胺（dys）调节上，因为儿茶酚胺在人和动物中都能调节多动症。我们发现儿茶酚胺调节缺陷是纹状体和伏隔核所特有的；去甲肾上腺素（NE）浓度显著升高，多巴胺（DA）利用率降低。脑内其他区域的NE和DA调节都是正常的。NE的增加可能有助于这些小鼠运动过度活跃的表达，因为NE的消耗改善了结肠瘤小鼠的运动过度活跃。这些结果为假设提供了强有力的证据，即在这种病理状态下，NE可能调节运动过动。在这种小鼠模型中，NE的异常调节特别相关，因为在ADHD和TS中已经发现了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.