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

描述（由申请人提供）：长期可塑性对纹状体的正常功能至关重要。它发生在几十分钟的时间尺度上，并且是习惯形成和学习的基础。长时程增强和长时程抑制之间的微妙平衡对于正确的运动和认知功能是重要的，并且在基于纹状体的疾病如帕金森病中被破坏（Calabresi等人，2007年）。许多分子是长期可塑性所必需的，但它们需要活跃的确切位置还没有很好地确定。环AMP依赖性蛋白激酶（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PKA，但PKA并不是随机地位于神经元内。PKA通过A-激酶锚定蛋白（AKAP）定位于神经元的特定区域。本研究探讨了PKA在皮质-纹状体LTP发生中的活跃位置.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磷酸化靶点或靠近cAMP来源的地方。我还将研究一种特定的AKAP（AKAP 150）的作用，AKAP 150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PKA在纹状体中的锚定是理解纹状体可塑性的细胞内信号级联的重要一步。对这些途径的全面了解将指导研究新的药物靶点，以解决帕金森病的运动和认知缺陷。 公共卫生相关性：神经元通路的增强和减弱之间的正确平衡对于正常的大脑功能至关重要。背侧纹状体中这种平衡的破坏可能是与帕金森病相关的运动和认知缺陷的原因。该项目将研究加强背侧纹状体通路的具体机制，并将产生有助于建立新的药物靶点和评估目前帕金森病治疗方法的信息。

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.