Targeting adenylyl cyclase to prevent L-DOPA-induced dyskinesia

描述(申请人提供)：L-多巴诱发的运动障碍(LID)帕金森氏病(PD)是由于皮质纹状体的异常可塑性。然而，晚期帕金森病患者长期服用L多巴是如何导致这种异常可塑性的仍不清楚。我们着重于这样一种假设，即调节时相多巴胺的释放改变了皮质纹状体突触的强度。在晚期帕金森病患者，L多巴可恢复多巴胺神经元的强直性多巴胺释放，但不能恢复因纹状体多巴胺终末丢失而调节的时相多巴胺释放。相反，L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途径在皮质纹状体可塑性中起重要作用。纹状体中主要的腺酰环化酶(AC)亚型是钙-钙调蛋白(CaCaM)不敏感的亚型AC5。因此，成年纹状体cAMP的产生依赖于G蛋白偶联受体。CaM缺乏对cAMP产生的刺激以及对G蛋白偶联受体激活的依赖，使得皮质纹状体的神经可塑性依赖于多巴胺的输入。我们已经产生了在纹状体神经元中表达CaCaM依赖的AC1的转基因小鼠。我们推测，在这些小鼠中，纹状体神经元中的cAMP通路将通过皮质谷氨酸能输入的CaCaM和NMDA受体激活而激活，而不依赖于多巴胺的输入。晚期帕金森病患者已失去大部分调节时相多巴胺的释放，多巴胺水平的大幅波动导致异常可塑性，多巴胺对异常可塑性的影响减弱将减弱多巴胺对运动障碍的作用。拟议的研究旨在为其对眼睑的潜在治疗作用提供原理证据。 公共卫生相关性：L-多巴引起的运动障碍是阿尔金森病治疗中的主要问题。我们将测试腺酰环化酶是一个有效的靶点，以改变皮质纹状体的可塑性和预防L-多巴诱发的运动障碍。

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.