Although cell transplantation can rescue motor defects in Parkinson’s disease (PD) models, whether and how grafts functionally repair damaged neural circuitry in the adult brain is not known. We transplanted hESC-derived midbrain dopamine (mDA) or cortical glutamate neurons into the substantia nigra or striatum of a mouse PD model and found extensive graft integration with host circuitry. Axonal pathfinding toward the dorsal striatum was determined by the identity of the grafted neurons, and anatomical presynaptic inputs were largely dependent on graft location, whereas inhibitory versus excitatory input was dictated by the identity of grafted neurons. hESC-derived mDA neurons display A9 characteristics and restore functionality of the reconstructed nigrostriatal circuit to mediate improvements in motor function. These results indicate similarity in cell-type-specific pre- and post-synaptic integration between transplant-reconstructed circuit and endogenous neural networks, highlighting the capacity of hPSC-derived neuron subtypes for specific circuit repair and functional restoration in the adult brain.

尽管细胞移植可以挽救帕金森病 (PD) 模型中的运动缺陷，但移植物是否以及如何在功能上修复成人大脑中受损的神经回路尚不清楚。我们将 hESC 衍生的中脑多巴胺 (mDA) 或皮质谷氨酸神经元移植到黑质中或小鼠 PD 模型的纹状体，并发现与宿主电路的广泛移植整合。朝向背侧纹状体的轴突寻路取决于移植神经元的身份，而解剖突触前输入很大程度上取决于移植位置，而抑制性与兴奋性输入则由移植神经元的身份决定。hESC 衍生的 mDA 神经元显示 A9 特征并恢复重建的黑质纹状体回路的功能，以介导运动功能的改善。这些结果表明移植重建电路和内源性神经网络之间细胞类型特异性突触前和突触后整合的相似性，突出了 hPSC 衍生的神经元亚型在成人大脑中特定电路修复和功能恢复的能力。