Preventing Experience Dependent Aberrant Plasticity Under Dopamine Deficiency

L多巴治疗早期帕金森病疗效显著。然而，随着慢性多巴胺替代疗法的进行，运动障碍等运动副作用成为晚期帕金森病的一个严重问题。帕金森病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上的研究首次表明，在低多巴胺条件下的经验依赖型异常运动学习(习得性运动抑制)可能在帕金森病患者的运动症状中起主要作用，这一点得到了最近对帕金森病患者的研究和计算模型的支持。此外，我们已经证明，谷氨酸能输入与多巴胺信号通过腺酰环化酶5型(AC5)和cAMP途径相结合，在表达多巴胺D2受体的纹状体中中棘神经元(MSN)中参与皮质纹状体长时程增强和抑制(LTP和LTD)。更重要的是，我们发现LTP异常与运动学习异常有关，而防止LTP异常与运动学习异常有关。我们在行为学和电生理学方面的进展为基于预防和/或逆转皮质纹状体LTP的潜在PD治疗方法的识别和测试奠定了基础。在这个应用中，我们建议测试在表达D2的MSN中诱导皮质纹状体LTP/LTD的精确条件/参数。然后，我们的目标是建立皮质纹状体LTP异常和运动学习异常之间的因果联系，并测试可以预防这种异常的皮质纹状体LTP和运动学习的治疗方法。 异常的运动学习。最后，我们将在帕金森病模型中检测其预防和逆转LTP异常的治疗作用。

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.