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58 reviewsSUMMARYA10 dopaminergic neurons located in the ventral tegmental area play central roles in reward-related and goaldirected behaviors and are proposed to be target cells for treatment of various psychiatric disorders,including depression. Here, we report an efficient differentiation method to generate A10-like midbrain dopaminergic (mDA) neurons from human pluripotent stem cells (hPSCs) and found that post-mitotic patterning byNotch inhibitor, glial cell line-derived neurotrophic factor (GDNF), and ascorbic acid (AA) induced A10 subtype specification. These hPSC-derived mDA neurons exhibited characteristics of the A10 subtype, includinggene expression profiles and electrophysiological properties. Moreover, grafted A10-like mDA neurons specifically project to their endogenous target brain regions and induce the anxiolytic phenotype in normal miceor antidepressant-like phenotypes in depression model mice. These results indicate that grafted A10-likemDA neurons can reconstruct specific circuits and functionally restore impaired circuits, highlighting thepromising application of hPSC-derived neuron subtypes in the treatment of neuropsychiatric disorders.
