Adenylyl cyclase and plasticity in the striatum.

描述（由申请人提供）：我的项目旨在研究记忆形成和维持中可塑性和稳定性之间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，这很容易形成和遗忘（即高度可塑性）。相反，依赖纹状体的记忆主要是程序性或运动性的习惯，这些习惯是逐渐形成的，很难消除（即高度稳定）。我推测腺苷酸环化酶（AC）在这种平衡中起着重要作用。AC1受到Ca/CaM的刺激，在海马中有高表达，但在纹状体中不存在，在纹状体中ACS是主要亚型。ACS受到Ca2+和蛋白激酶A的抑制，这是突触可塑性的两个组成部分。我推测，由于ACS的表达，纹状体中cAMP的产生受到限制，导致突触可塑性降低，从而使依赖纹状体的记忆更加稳定。我建议用一种转基因方法来验证这一点：在纹状体中表达AC1。我将用生物化学方法测试这些老鼠的突触可塑性，以及在解剖纹状体依赖性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治疗与运动习惯相关的疾病（包括图雷特综合症、强迫症和成瘾）至关重要。

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.