Adenylyl cyclase and plasticity in the striatum.

描述(由申请者提供)：我的项目旨在调查记忆形成和维持中的可塑性和稳定性之间的平衡的神经生物学基础。在哺乳动物中，海马体依赖的记忆主要是陈述性的，很容易形成和遗忘(即高度可塑性)。相比之下，纹状体依赖的记忆主要是程序性或运动性习惯，这些习惯是逐渐形成的，很难消除(即高度稳定)。我推测腺酰环化酶(AC)在这种平衡中起着重要的作用。AC1受钙/钙调素的刺激，在海马区高表达，但在纹状体中不表达，而纹状体中AC1是主要的亚型。突触可塑性的两个组成部分--钙离子和蛋白激酶A对ACS有抑制作用。我推测，由于ACS的表达，纹状体内cAMP的产生受到限制，导致突触可塑性降低，从而使纹状体依赖记忆更加稳定。我建议使用一种转基因方法来测试这一点：在纹状体中表达AC1。我将对这些小鼠进行生物化学测试，看看它们在突触可塑性方面的表现，以及在剖析纹状体依赖记忆的任务中的行为。就这项研究与公共卫生的相关性而言，了解皮质纹状体可塑性的基础对于开发与运动习惯相关的疾病的治疗方法至关重要，这些疾病包括抽动症、强迫症和成瘾。

DESCRIPTION (provided by applicant): My project aims to investigate the neurobiological bases that underlie the balance between plasticity and stability in memory formation and maintenance. In mammals, hippocampus-dependent memory is mainly declarative, which is easy to form and forget (i.e. highly plastic). In contrast, striatum-dependent memory is mainly procedural or motor habits which form incrementally and hard to extinguish (i.e. highly stable). I hypothesize that adenylyl cyclases (AC) play an important role in this balance. AC1 is stimulated by Ca/CaM, and has high expression in the hippocampus, but is absent in the striatum, where ACS is the primary isoform. ACS is inhibited by Ca2+ and protein kinase A, two integral components of synaptic plasticity. I hypothesize that due to expression of ACS, there is a constraint on cAMP production in the striatum, causing reduced synaptic plasticity, and thus making striatum dependent memories more stable. I propose to test this using a transgenic approach: expressing AC1 in the striatum. I will test these mice biochemically for players in synaptic plasticity, and behaviorally in tasks that dissect striatum dependent memory. In terms of relevance of this research to public health, understanding the basis for corticostriatal plasticity is crucial for developing therapies for motorhabits related disorders that include Tourette Syndrome, obsessive compulsive disorder and addiction.