Synapsin 3: Involvement in Impulsivity and Drug Self-Administration

描述（由申请人提供）：难以抑制或抑制强效前行为（“冲动”或冲动行为的一个维度）与人类药物和酒精使用障碍的风险增加以及动物模型中药物自我给药表型的增加有关。最近的研究表明，冲动行为与多巴胺D2受体敏感的皮质纹状体网络的变化有关，两者都受到迄今未知的遗传机制的影响。我们在近交小鼠中使用全基因组连锁方法来鉴定冲动性的新基因调节因子，我们鉴定了编码突触蛋白III的syn3，作为一个非常优先的候选基因。随后我们发表的研究表明，syn3可能通过其在多巴胺能神经末梢的定位和功能来控制多巴胺释放事件的幅度。基于所有这些信息，我们现在测试新的高风险假设，即多巴胺能神经元内syn3的表达影响：1)多巴胺释放，2)突触后d2样受体的表达，3)抑制控制和4)药物自我给药。利用一种新的条件模型，允许全脑或多巴胺神经元特异性的syn3缺失，我们试图通过实验测试该基因在这些不同表型中的作用，进而确定其在调节成瘾的一系列生物学和行为内表型中的关键作用。这些高风险研究提供了一个机会，以确定一个新的候选风险基因对成瘾的重要性，支持在人类和动物模型中对突触蛋白III及其与药物滥用易感性的联系进行更系统的多层次研究。这些研究也将为深入的机制研究奠定基础，旨在了解改变的多巴胺能传递如何因果影响冲动控制和药物自我给药。

DESCRIPTION (provided by applicant): Difficulty suppressing or inhibiting pre-potent behaviors (one dimension of 'impulsivity' or impulsive behaviors) has been associated with elevated risk for drug and alcohol use disorders in humans and with heightened drug self-administration phenotypes in animal models. Recent work indicates that impulsive behaviors are linked to changes in dopamine D2 receptor- sensitive corticostriatal networks and that both are under the influence of as-of-yet unknown genetic mechanisms. We have used a genome-wide linkage approach in inbred mice to identify novel gene modulators of impulsivity, and we identified syn3, which encodes synapsin III, as a very high priority candidate gene. Subsequent to our published study, it was shown that syn3 controls the amplitude of dopamine release events, presumably through its localization and functions in dopaminergic nerve terminals. Based upon all this information, we now test the novel and high-risk hypothesis that syn3 expression within dopaminergic neurons influences: 1) dopamine release, 2) expression of post-synaptic D2-like receptors, 3) inhibitory control and 4) drug self-administration. Using a newly available conditional model that allows for brain-wide or dopamine neuron-specific deletion of syn3, we seek to experimentally test the role for this gene in these varied phenotypes, in turn establishing its key role in regulating a series of biological and behavioral endophenotypes for addiction. These high-risk studies offer an opportunity to establish the significance of a novel candidate risk gene for addictions, supporting more systematic multi-level studies in humans and animal models regarding synapsin III and its link to drug abuse susceptibility. These studies will also set the stage for in depth, mechanistic studies aimed at understanding how altered dopaminergic transmission causally influences impulse control and drug self-administration.