The projection-specific signals that establish functionally segregated dopaminergic synapses

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...

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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
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Summary: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.
ISSN:0092-8674
1097-4172
1097-4172
DOI:10.1016/j.cell.2023.07.023