Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, USA; Department of Neurology, UAB, Birmingham, AL, USA.
Center for Neurodegeneration and Experimental Therapeutics, Birmingham, AL, USA; Department of Neurology, UAB, Birmingham, AL, USA.
Neurobiol Dis. 2024 Oct 15;201:106685. doi: 10.1016/j.nbd.2024.106685. Epub 2024 Sep 27.
Altered interaction between striatonigral dopaminergic (DA) inputs and local acetylcholine (ACh) in striatum has long been hypothesized to play a central role in the pathophysiology of dystonia and dyskinesia. Indeed, previous research using several genetic mouse models of human isolated dystonia identified a shared endophenotype with paradoxical excitation of striatal cholinergic interneuron (ChIs) activity in response to activation of dopamine D2 receptors (D2R). These mouse models lack a dystonic motor phenotype, which leaves a critical gap in comprehending the role of DA and ACh transmission in the manifestations of dystonia. To tackle this question, we used a combination of ex vivo slice physiology and in vivo monitoring of striatal ACh dynamics in the inducible, phenotypically penetrant, transgenic mouse model of paroxysmal non-kinesiogenic dyskinesia (PNKD), an animal with both dystonic and dyskinetic features. We found that, similarly to genetic models of isolated dystonia, the PNKD mouse displays D2R-induced paradoxical excitation of ChI firing in ex vivo striatal brain slices. In vivo, caffeine triggers dystonic symptoms while reversing the D2R-mediated excitation of ChIs and desynchronizing ACh release in PNKD mice. In WT littermate controls, caffeine stimulates spontaneous locomotion through a similar but reversed mechanism involving an excitatory switch of the D2R control of ChI activity, associated with enhanced synchronization of ACh release. These observations suggest that the "paradoxical excitation" of cholinergic interneurons described in isolated dystonia models could represent a compensatory or protective mechanism that prevents manifestation of movement abnormalities and that phenotypic dystonia is possible only when this is absent. These findings also suggest that D2Rs may play an important role in synchronizing the ChI network leading to rhythmic ACh release during heightened movement states. Dysfunction of this interaction and corresponding desynchrony of ACh release may contribute to aberrant movements.
纹状体中纹状体黑质多巴胺能（DA）输入和局部乙酰胆碱（ACh）之间的相互作用改变，长期以来一直被认为在肌张力障碍和运动障碍的病理生理学中起核心作用。事实上，使用几种人类孤立性肌张力障碍的遗传小鼠模型进行的先前研究确定了一种共同的表型内表型，即对多巴胺 D2 受体（D2R）激活的纹状体内胆碱能中间神经元（ChIs）活性的反常兴奋。这些小鼠模型缺乏肌张力障碍运动表型，这使得理解 DA 和 ACh 传递在肌张力障碍表现中的作用存在关键差距。为了解决这个问题，我们使用了离体切片生理学和诱导型、表型渗透的转基因小鼠模型（PNKD）中纹状体内 ACh 动力学的体内监测的组合，这种动物既有肌张力障碍又有运动障碍的特征。我们发现，与孤立性肌张力障碍的遗传模型类似，PNKD 小鼠在离体纹状脑切片中显示 D2R 诱导的 ChI 放电反常兴奋。在体内，咖啡因会引发肌张力障碍症状，同时逆转 D2R 介导的 ChI 兴奋并使 PNKD 小鼠中的 ACh 释放去同步。在 WT 同窝对照中，咖啡因通过一种类似但相反的机制刺激自发运动，该机制涉及 D2R 对 ChI 活性的兴奋性转换，与 ACh 释放的增强同步有关。这些观察结果表明，在孤立性肌张力障碍模型中描述的“反常兴奋”胆碱能中间神经元可能代表一种补偿或保护机制，可防止运动异常的表现，并且只有当这种机制不存在时，才会出现表型性肌张力障碍。这些发现还表明，D2R 可能在协调导致运动状态增强时的节律性 ACh 释放的 ChI 网络中起重要作用。这种相互作用的功能障碍和相应的 ACh 释放失同步可能导致异常运动。
