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The projection-specific signals that establish functionally segregated dopaminergic synapses

四川生理科学杂志 2023年第9期45卷 1742-1742页

作者： akiko terauchi Department of Neurology F.M. Kirby Neurobiology Center Boston Children’s Hospital Harvard Medical School Boston MA 02115 USA Department of Neurobiology and Howard Hughes Medical Institute Harvard Medical School Boston MA 02115 USA Department of Computer Science Northern Illinois University DeKalb IL 60115 USA State Key Laboratory of Membrane Biology PKU-IDG/McGovern Institute for Brain Research Peking-Tsinghua Center for Life Sciences Peking University Beijing 100871 China

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, whichcontrols 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.

关键词： projection motivation specific

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