The projection-specific signals that establish functionally segregated dopaminergic synapses

• Published in: Cell 2023-08, Vol.186 (18), p.3845-3861.e24
• Main Authors: Terauchi, Akiko, Yee, Patricia, Johnson-Venkatesh, Erin M., Seiglie, Mariel P., Kim, Lisa, Pitino, Julia C., Kritzer, Eli, Zhang, Qiyu, Zhou, Jie, Li, Yulong, Ginty, David D., Lee, Wei-Chung A., Umemori, Hisashi
• Format: Article
• Language: English
• Subjects: Animals; BMP vs. TGF-β signaling; bone morphogenetic protein vs. transforming growth factor β signaling; Corpus Striatum; Dopamine; Mesencephalon; Mice; Motivation; Movement; nigrostriatal and mesolimbic dopaminergic projections; Parkinson’s disease; schizophrenia and depression; synapse development and function; Synapses
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2023.07.023

Dopaminergic projections regulate various brain functions and are implicated in many neuropsychiatric disorders. There are two anatomically and functionally distinct dopaminergic projections connecting the midbrain to striatum: nigrostriatal, which controls movement, and mesolimbic, which regulates motivation. However, how these discrete dopaminergic synaptic connections are established is unknown. Through an unbiased search, we identify that two groups of antagonistic TGF-β family members, bone morphogenetic protein (BMP)6/BMP2 and transforming growth factor (TGF)-β2, regulate dopaminergic synapse development of nigrostriatal and mesolimbic neurons, respectively. Projection-preferential expression of their receptors contributes to specific synapse development. Downstream, Smad1 and Smad2 are specifically activated and required for dopaminergic synapse development and function in nigrostriatal vs. mesolimbic projections. Remarkably, Smad1 mutant mice show motor defects, whereas Smad2 mutant mice show lack of motivation. These results uncover the molecular logic underlying the proper establishment of functionally segregated dopaminergic synapses and may provide strategies to treat relevant, projection-specific disease symptoms by targeting specific BMPs/TGF-β and/or Smads. [Display omitted] •An unbiased search identified projection-specific dopaminergic synaptic organizers•BMP6/2–Smad1 and TGF-β2–Smad2 axes establish nigrostriatal vs. mesolimbic synapses•BMP6, BMP2, and TGF-β2 synergize or antagonize to establish dopaminergic synapses•Smad1 mutant mice show motor defects, and Smad2 mutant mice show a lack of motivation Dopaminergic synapse formation of nigrostriatal and mesolimbic neurons is determined by distinct BMP6/2–Smad1 and TGF-β2–Smad2 pathways.