Dopamine-Dependent Compensation Maintains Motor Behavior in Mice with Developmental Ablation of Dopaminergic Neurons
Dopamine-Dependent Compensation Maintains Motor Behavior in Mice with Developmental Ablation of Dopaminergic Neurons
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DOI：
10.1523/jneurosci.0890-13.2013
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发表时间：
2013-10-23
影响因子：
5.3
通讯作者：
Jain, Sanjay
中科院分区：
文献类型：
--
作者：
Golden, Judith P.;DeMaro, Joseph A., III;Jain, Sanjay
在黑质的多巴胺能神经元的损失和随之而来的纹状体多巴胺的耗竭是已知的帕金森氏病（PD）中观察到的运动缺陷的基础。多巴胺能末梢和突触后纹状体神经元的适应性变化可以补偿纹状体多巴胺的显著损失，从而保护运动行为。此外，已经提出了独立于纹状体多巴胺的代偿性变化，其基于调节基底神经节内非多巴胺能回路的PD疗法。我们使用了一种遗传策略，在发育过程中选择性地破坏小鼠的多巴胺能神经元，以确定这些神经元维持成年和老年小鼠正常运动行为的必要性。我们发现，90%的SNc多巴胺能神经元的损失和随后的>95%的纹状体多巴胺的消耗不会导致成年或老年小鼠的运动行为的变化，如通过大量的运动行为测试所评估的。用多巴胺受体拮抗剂氟哌啶醇治疗老年突变小鼠会导致老年突变小鼠的运动行为缺陷，这表明，
The loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and consequent depletion of striatal dopamine are known to underlie the motor deficits observed in Parkinson's disease (PD). Adaptive changes in dopaminergic terminals and in postsynaptic striatal neurons can compensate for significant losses of striatal dopamine, resulting in preservation of motor behavior. In addition, compensatory changes independent of striatal dopamine have been proposed based on PD therapies that modulate nondopaminergic circuits within the basal ganglia. We used a genetic strategy to selectively destroy dopaminergic neurons in mice during development to determine the necessity of these neurons for the maintenance of normal motor behavior in adult and aged mice. We find that loss of 90% of SNc dopaminergic neurons and consequent depletion of >95% of striatal dopamine does not result in changes in motor behavior in young-adult or aged mice as evaluated by an extensive array of motor behavior tests. Treatment of aged mutant mice with the dopamine receptor antagonist haloperidol precipitated motor behavior deficits in aged mutant mice, indicating that