Transmitter release in a model of hyperactivity

超出所提供的空间。 在几种神经系统疾病中观察到病理性多动，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，从而了解病理性多动的病因。我们已经确定了小鼠突变体缺损作为一种新的动物模型的多动症。这些小鼠极度活跃，自发活动超过其对照同窝小鼠的3倍。我们已经证明，由缺损小鼠表达的活动过度明显是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质，其是在突触前膜处停靠和保持突触囊泡以准备好用于Ca 2+触发的神经递质胞吐的机制的必要组成部分。虽然SNAP-25在所有神经元中表达，但我们的实验集中在儿茶酚胺（dys）调节上，因为已知儿茶酚胺调节人和动物的多动症。我们已经发现，在儿茶酚胺调节的缺陷是特定的纹状体和丘脑核，去甲肾上腺素（NE）的浓度显着增加，而多巴胺（DA）的利用率下降。NE和DA调节在所有其他脑区中是正常的。NE的增加可能有助于这些小鼠中运动过度活跃的表达，因为NE的消耗改善了缺损小鼠的过度活跃。这些结果提供了强有力的证据的假设，在这种病理状态下，NE可以调节运动过度活跃。在该小鼠模型中NE的异常调节是特别相关的，因为在ADHD和TS中已经鉴定出NE的异常。性能现场=

EXCEED THE SPACE PROVIDED. 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. PERFORMANCE SITE ========================================Section End===========================================