The Role of PKA Activity and AKAP anchoring in Striatal Synaptic Plasticity

描述(申请人提供)：长期可塑性对于纹状体的正常功能是必不可少的。它发生在几十分钟的时间尺度上，被认为是养成习惯和学习的基础。长期增强和长期抑郁之间的微妙平衡对于正确的运动和认知功能很重要，在以纹状体为基础的疾病中，如帕金森氏病，这种平衡被打破(Calabresi等人，2007年)。许多分子是长期可塑性所必需的，但它们到底需要在哪里发挥作用还没有得到很好的确定。环磷酸腺苷依赖蛋白激酶(PKA)就是这样一种分子。纹状体突触的长时程增强(LTP)需要激活的PKA，但PKA不是随机分布在神经元内的。PKA通过A-激酶锚定蛋白(AKAP)定位于神经元的特定区域。这项研究调查了PKA必须在哪里活跃才能发生皮质-纹状体LTP。利用电生理学、药理学和转基因小鼠，我将测试PKA是否需要在突触前或突触后锚定，以及它是否需要集中在靠近其磷酸化目标或接近cAMP来源的地方。我还将研究一种特殊的AKAP，AKAP150，它与纹状体学习任务有关，但其在皮质-纹状体可塑性中的作用尚不清楚(Weisenhaus等人，2010年)。深入分析纹状体中PKA的锚定是理解纹状体可塑性背后的细胞内信号级联的关键一步。对这些途径的全面了解将指导研究开发新的药物靶点，以解决帕金森氏症的运动和认知缺陷。 与公共健康相关：神经元通路的加强和减弱之间的正确平衡对正常的大脑功能至关重要。背侧纹状体这种平衡的破坏可能是与帕金森氏症相关的运动和认知障碍的原因。该项目将研究背侧纹状体通路增强的具体机制，并将提供有助于建立新的药物靶点和评估目前帕金森氏病治疗方法的信息。

DESCRIPTION (provided by applicant): Long term plasticity is essential for the proper function of the striatum. It occurs on a timescale of tens of minutes and putatively underlies habit formation and learning. The delicate balance between long term potentiation and long term depression is important for correct motor and cognitive function and is disrupted in striatal based diseases such as Parkinson's Disease (Calabresi et al., 2007). Many molecules are necessary for long term plasticity, but exactly where they need to be active is not well established. Cyclic AMP dependent protein kinase (PKA) is one such molecule. Long term potentiation (LTP) of striatal synapses requires active PKA, but PKA is not randomly located within a neuron. PKA is localized to specific areas of the neuron by A-kinase anchoring proteins (AKAPs). This study investigates where PKA must be active for cortico- striatal LTP to occur. Using electrophysiology, pharmacology, and transgenic mice, I will test whether PKA needs to be anchored pre- or post-synaptically, and whether it needs to be concentrated close to its phosphorylation targets or close to the source of cAMP. I will also investigate the role of one particular AKAP, AKAP150, which has been implicated in striatal learning tasks, but whose role in cortico-striatal plasticity is unknown (Weisenhaus et al., 2010). An in-depth analysis of PKA anchoring in the striatum is an essential step in understanding the intracellular signaling cascades that underlie striatal plasticity. A complete understanding of these pathways will guide research to novel drug targets that address both the motor and the cognitive deficits of Parkinson's Disease. PUBLIC HEALTH RELEVANCE: The correct balance between the strengthening and weakening of neuronal pathways is essential for proper brain function. A disruption of this balance in the dorsal striatum may be the cause of motor and cognitive deficits associated with Parkinson's Disease. This project will examine specific mechanisms underlying the strengthening of dorsal striatum pathways and will yield information helpful for establishing new drug targets and evaluating current treatments for Parkinson's Disease.