Targeting adenylyl cyclase to prevent L-DOPA-induced dyskinesia

描述（由申请人提供）：帕金森病（PD）中左旋多巴诱导的运动障碍（LID）是由于异常的皮质纹状体可塑性所致。然而，慢性左旋多巴治疗晚期PD如何导致这种异常的可塑性仍然未知。我们专注于这一假设，这是调节阶段性多巴胺释放，修改皮质纹状体突触强度。在晚期PD中，L-DOPA能够恢复紧张性多巴胺，但由于纹状体中多巴胺终末的丢失，不能调节多巴胺神经元的阶段性多巴胺释放。相反，由于左旋多巴治疗引起的多巴胺释放的不受调节的波动将导致皮质纹状体突触强度和LID的异常改变。cAMP通路在皮质纹状体可塑性中起重要作用。纹状体中的主要腺苷酸环化酶（AC）同种型是钙-钙调蛋白（CaCaM）不敏感的同种型AC 5。因此，成年纹状体中cAMP的产生依赖于G蛋白偶联受体。这种缺乏CaCaM刺激cAMP产生及其对G蛋白偶联受体激活的依赖使得皮质纹状体神经可塑性依赖于多巴胺输入。我们已经产生了转基因小鼠表达的钙钙调素依赖的AC 1在纹状体神经元。我们推测，在这些小鼠中，纹状体神经元中的cAMP通路将通过CaCaM和NMDA受体激活，而不依赖于多巴胺输入。在晚期PD患者中，已经失去了大部分调节的阶段性多巴胺释放和多巴胺水平的大幅波动有助于异常可塑性，多巴胺对异常可塑性的影响的减弱将减弱多巴胺对运动障碍的作用。拟定的研究旨在为其对LID的潜在治疗作用提供原理证明。 公共卫生相关性：左旋多巴引起的运动障碍是帕金森病治疗中的一个主要问题。我们将测试腺苷酸环化酶是一个有效的目标，修改皮质纹状体可塑性和防止左旋多巴诱导的运动障碍。

DESCRIPTION (provided by applicant): L-DOPA-induced dyskinesia (LID) in Parkinson's isease (PD) is due to aberrant corticostriatal plasticity. However, how chronic L-DOPA treatment in advanced stage PD causes such aberrant plasticity remains unknown. We focus on the hypothesis that it is the regulated phasic dopamine release that modifies corticostriatal synaptic strength. In advanced stage PD, L-DOPA is able to restore tonic dopamine but not regulated phasic dopamine release from dopamine neurons due to the loss of dopamine terminals in the striatum. Instead, unregulated fluctuations in dopamine release due to L-DOPA therapy will cause aberrant modification of corticostriatal synaptic strength and LID. cAMP pathway is important for corticostriatal plasticity. The main adenylyl cyclase (AC) isoform in the striatum is the calcium-calmodulin (CaCaM)- insensitive isoform AC5. Accordingly, cAMP production in adult striatum relies on G protein coupled receptors. Such a lack of CaCaM stimulation of cAMP production and its reliance on G protein coupled receptor activation makes corticostriatal neuroplasticity dependent on dopamine input. We have generated transgenic mice that express the CaCaM-dependent AC1 in striatal neurons. We hypothesize that in these mice, cAMP pathway in striatal neurons will be activated through CaCaM and NMDA receptor activation from cortical glutamatergic input independent of dopamine input. In advanced stage PD patients who have already lost most of regulated phasic dopamine release and wide fluctuations of dopamine levels contribute to aberrant plasticity, attenuation of dopamine influence on the aberrant plasticity will blunt the effect of dopamine on dyskinesia. The proposed studies aim to provide proof of principle for its potential therapeutic effects on LID. PUBLIC HEALTH RELEVANCE: L-DOPA-induced dyskinesia is a main problem in arkinson's disease therapy. We will test that adenylyl cyclase is a valid target for modifying corticostriatal plasticity and preventing L-DOPA induced dyskinesia.