Wang Qian, Wang Yuhan, Liao Francesca-Fang, Zhou Fu-Ming
Department of Pharmacology, Addiction Science and Toxicology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN 38103, USA.
Brain Sci. 2025 Sep 12;15(9):979. doi: 10.3390/brainsci15090979.
Despite the profound behavioral effects of the striatal dopamine (DA) activity and the inwardly rectifying potassium channel (Kir) being a key determinant of striatal medium spiny neuron (MSN) activity that strongly affects behavior, previously reported DA regulations of Kir are conflicting and incompatible with MSN function in behavior. Here, we used DA depletion mouse models that have hyperfunctional DA receptors such that potential DA regulation of Kir may be enhanced and relatively large and thus detected reliably. We show that in striatal brain slices from normal mice with an intact striatal DA system, the predominant effect of DA activation of D1Rs in D1-MSNs is to cause a modest depolarization and an increase in input resistance by inhibiting Kir, thus moderately increasing the spike outputs from behavior-promoting D1-MSNs. In brain slices from parkinsonian (DA-depleted) striatum, DA increases D1-MSN intrinsic excitability more strongly than in normal striatum, consequently more strongly increasing D1-MSN spike firing that is behavior-promoting. This DA inhibition of Kir is occluded by the Kir blocker barium chloride (BaCl). In behaving parkinsonian mice, BaCl microinjection into the dorsal striatum stimulates movement and also occludes the motor stimulation of D1R agonism. Taken together, our results resolve the long-standing question about what D1R agonism does to D1-MSN excitability in normal and parkinsonian striatum and strongly indicate that D1R inhibition of Kir is a key ion channel mechanism that mediates the profound motoric and behavioral stimulation of striatal D1R activation in normal and parkinsonian animals.
尽管纹状体多巴胺（DA）活性具有深远的行为效应，且内向整流钾通道（Kir）是纹状体中等棘状神经元（MSN）活性的关键决定因素，强烈影响行为，但先前报道的DA对Kir的调节存在冲突，且与MSN在行为中的功能不兼容。在此，我们使用了具有超功能DA受体的DA耗竭小鼠模型，使得Kir潜在的DA调节可能增强且相对较大，从而能够可靠地检测到。我们表明，在具有完整纹状体DA系统的正常小鼠的纹状体脑片中，D1-MSNs中D1Rs的DA激活的主要作用是通过抑制Kir引起适度的去极化和输入电阻增加，从而适度增加促进行为的D1-MSNs的尖峰输出。在帕金森病（DA耗竭）纹状体的脑片中，DA比在正常纹状体中更强烈地增加D1-MSN的内在兴奋性，因此更强烈地增加促进行为的D1-MSN尖峰放电。DA对Kir的这种抑制作用被Kir阻断剂氯化钡（BaCl）所阻断。在行为的帕金森病小鼠中，向背侧纹状体微量注射BaCl会刺激运动，并且也会阻断D1R激动剂的运动刺激作用。综上所述，我们的结果解决了一个长期存在的问题，即D1R激动剂对正常和帕金森病纹状体中D1-MSN兴奋性的影响，并且有力地表明D1R对Kir的抑制是一种关键的离子通道机制，介导了正常和帕金森病动物中纹状体D1R激活所产生的深刻运动和行为刺激。
