Animal models of dopamine-independent motor control

描述(申请人提供)：在帕金森氏病(PD)中，多巴胺替代疗法在最初几年效果良好。然而，在帕金森病晚期，这样的治疗会导致运动障碍，通常比帕金森病本身更令人虚弱。迫切需要开发替代方法来治疗运动障碍。我们最近发现，纹状体富集腺酰环化酶(AC)V型(AC5)缺陷的小鼠表现出多巴胺D2受体非依赖的运动控制。然而，它们仍然依赖于多巴胺D1受体。我们推测，纹状体D1R阳性神经元中腺苷酸环化酶I型(AC1)的过度表达将使D1R非依赖的运动控制。我们进一步假设，双转基因小鼠在D1神经元中AC1过度表达和AC5缺乏将表现出多巴胺非依赖性运动控制。我们建议产生这些转基因小鼠，并使用多巴胺拮抗剂、多巴胺耗竭和多巴胺神经元损伤来验证我们的假设。我们将使用运动活动、运动迟缓测试、步态分析和旋转棒来检查运动功能。 公共卫生相关性：我们将产生具有多巴胺非依赖性运动控制的转基因小鼠。阳性结果将提供原则证据，并将指导以非多巴胺替代为基础的帕金森病治疗方法的发展。

DESCRIPTION (provided by applicant): In Parkinson's disease (PD), dopamine replacement therapies work well for the first a few years. However, in late stage PD, such therapies cause dyskinesia that is often more debilitating than PD itself. There is an urgent need to develop alternative approaches to treat motor impairment. We recently found that mice deficient for the striatum enriched adenylyl cyclase (AC) type V (AC5) display dopamine D2 receptor- independent motor control. However they are still dependent on dopamine D1 receptors. We hypothesize that over-expression of adenylyl cyclase type I (AC1) in striatal D1 receptor positive neurons will enable D1 receptor-independent motor control. We further hypothesize that double transgenic mice with both AC1 over-expression in D1 neurons and AC5 deficiency will display dopamine-independent motor control. We propose to generate these transgenic mice and test our hypotheses using dopamine antagonists, dopamine depletion and dopamine neuron lesions. We will examine motor functions using locomotor activity, akinesia test, gait analysis and rotarod. PUBLIC HEALTH RELEVANCE: We will generate transgenic mice with dopamine-independent motor control. Positive results will provide proof of principle and will guide the development of non- dopamine replacement based therapies for Parkinson's disease.