Loss-of-function mutations in the parkin-encoding PARK2 gene are a frequent cause of young-onset, autosomal recessive Parkinson's disease (PD). Parkin knockout mice have no nigro-striatal neuronal loss but exhibit abnormalities of striatal dopamine transmission and cortico-striatal synaptic function. How these predegenerative changes observed in vitro affect neural dynamics at the intact circuit level, however, remains hitherto elusive. Here, we recorded from motor cortex, striatum and globus pallidus (GP) of anesthetized parkin-deficient mice to assess cortex-basal ganglia circuit dynamics and to dissect cell type-specific functional connectivity in the presymptomatic phase of genetic PD. While ongoing activity of presumed striatal spiny projection neurons and their downstream counterparts in the GP was not different from controls, parkin deficiency had a differential impact on striatal interneurons: In parkin-mutant mice, tonically active neurons displayed elevated activity levels. Baseline firing rates of transgenic striatal fast spiking interneurons (FSI), on the contrary, were reduced and the correlational structure of the FSI microcircuitry was disrupted. The entire transgenic striatal microcircuit showed enhanced and phase-shifted phase coupling to slow (1-3 Hz) cortical population oscillations. Unexpectedly, local field potentials recorded from striatum and GP of parkin-mutant mice robustly displayed amplified beta oscillations (~22 Hz), phase-coupled to cortex. Parkin deficiency selectively increased spike-field coupling of FSIs to beta oscillations. Our findings suggest that loss of parkin function leads to amplifications of synchronized cortico-striatal oscillations and an intrastriatal reconfiguration of interneuronal circuits. This presymptomatic disarrangement of dynamic functional connectivity may precede nigro-striatal neurodegeneration and predispose to imbalance of striatal outflow accompanying symptomatic PD.

中文翻译：

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帕金缺乏症扰乱了纹状体的动力学。

帕金编码的PARK2基因的功能丧失突变是年轻的常染色体隐性帕金森氏病（PD）的常见原因。帕金森基因敲除小鼠没有黑质纹状体神经元损失，但表现出纹状体多巴胺传递和皮质-纹状体突触功能异常。迄今为止，体外观察到的这些变性前变化如何影响完整回路水平的神经动力学。在这里，我们记录了麻醉的帕金缺乏症小鼠的运动皮层，纹状体和苍白球（GP），以评估皮层基底神经节回路的动力学，并剖析遗传PD症状前阶段特定于细胞类型的功能连接性。虽然假定的纹状体棘突神经元及其下游对应物在GP中的持续活动与对照组无差异，帕金缺乏症对纹状体中神经有不同的影响：在帕金突变小鼠中，具有音调活性的神经元显示出较高的活性水平。相反，降低了转基因纹状体快速加标中枢神经元（FSI）的基线发射率，并破坏了FSI微电路的相关结构。整个转基因纹状体微电路显示出增强的相移和相移，以缓慢（1-3 Hz）皮质种群振荡。出乎意料的是，从Parkin突变小鼠的纹状体和GP记录的局部电场势能强劲地显示出放大的β振荡（〜22 Hz），并与皮层相耦合。帕金缺乏症选择性地增加了FSI与β振荡的尖峰场耦合。我们的发现表明，Parkin功能的丧失会导致同步的皮层纹状体振荡和神经内回路的纹状体内重构。动态功能连接的这种症状前紊乱可能在黑纹状体纹状体神经变性之前发生，并易于伴随有症状的PD导致纹状体流出不平衡。