Preventing Experience Dependent Aberrant Plasticity Under Dopamine Deficiency

左旋多巴对早期帕金森病（PD）的治疗效果显著。然而，随着慢性多巴胺替代疗法，运动副作用如运动障碍成为晚期PD的严重问题。PD症状和治疗的潜在机制仍然知之甚少。我们最近在动物模型中的研究首次表明，低多巴胺条件下的经验依赖性异常运动学习（学习性运动抑制）可能在PD运动症状中起主要作用，这一点得到了最近对PD患者的研究和计算模型的支持。 此外，我们已经证明，通过腺苷酸环化酶5型（AC 5）和cAMP通路与多巴胺信号相结合的多巴胺能输入有助于皮质纹状体长时程增强和抑郁症（LTP和LTD）在多巴胺D2受体表达的纹状体中型棘神经元（MSN）。更重要的是，我们发现异常LTP与异常运动学习相关，而预防这种异常LTP与预防异常运动学习相关。我们的行为和电生理学进展为识别和测试基于预防和/或逆转异常皮质纹状体LTP的潜在PD疗法奠定了基础。在本申请中，我们建议测试在D2表达MSN中诱导皮质纹状体LTP/LTD的精确条件/参数。然后，我们的目标是建立异常皮质纹状体LTP和异常运动学习之间的因果关系，以及测试可以预防这种异常皮质纹状体LTP和异常运动学习的治疗方法。 异常运动学习最后，我们将测试在PD模型中预防和逆转异常LTP的治疗效果。

The therapeutic effects of L-DOPA are remarkable in early stage Parkinson's disease (PD). However, with chronic dopamine replacement therapy, motor side effects such as dyskinesia become a severe problem in advanced PD. Mechanisms underlying PD symptoms and therapy are still poorly understood. Our recent studies in animal models have for the first time demonstrated that experience-dependent aberrant motor learning (learned motor inhibition) under low dopamine conditions may play a major role in PD motor symptoms, which was supported by recent studies on PD patients and by computational models. Moreover, we have demonstrated that glutamatergic inputs in combination with dopamine signaling through the adenylyl cyclase type 5 (AC5) and the cAMP pathway contributes to corticostriatal long-term potentiation and depression (LTP and LTD) in the dopamine D2 receptor-expressing striatal medium spiny neurons (MSNs). More importantly, we have found that aberrant LTP is associated with aberrant motor learning while prevention of such aberrant LTP is associated with prevention of aberrant motor learning. Our behavioral and electrophysiological advances have set the stage for identifying and testing potential PD therapies based on preventing and/or reversing aberrant corticostriatal LTP. In this application, we propose to test the precise conditions/parameters for induction of corticostriatal LTP/LTD in D2-expressing MSNs. We then aim to establish a causal link between aberrant corticostriatal LTP and aberrant motor learning as well as to test treatments that can prevent such aberrant corticostriatal LTP and aberrant motor learning. Finally, we will test the therapeutic effects of preventing and reversing aberrant LTP in PD models.