Engineered synaptic tools reveal localized cAMP signaling in synapse assembly.
Engineered synaptic tools reveal localized cAMP signaling in synapse assembly.
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DOI：
10.1083/jcb.202109111
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发表时间：
2022-02-07
期刊：
影响因子：
--
通讯作者：
Südhof TC
中科院分区：
文献类型：
--
作者：
Sando R;Ho ML;Liu X;Südhof TC
在哺乳动物大脑发育过程中，不同的突触连接如何自组装成功能性神经回路的局部信号机制仍然未知。这项研究开发了分子工具，用于在突触形成过程中将信号扰动靶向定义的新生突触隔室。这些工具揭示了分隔化的突触后cAMP信号在驱动兴奋性突触组装中的重要作用。驱动突触形成的生理机制是难以捉摸的。尽管已知有许多信号调节突触，但仍不清楚哪些信号机制组织初始突触组装。在这里，我们描述了新的工具，称为“SynTAMs”的突触靶向分子，使本地化的cAMP信号在开发突触后专业化的扰动。我们发现，局部限制抑制突触后cAMP水平或cAMP依赖性蛋白激酶活性严重损害兴奋性突触的形成，而不影响神经元的成熟，树突状分支，或抑制性突触的形成。在体内，抑制CA 1神经元突触后cAMP信号传导阻止了Schaffer侧支和内鼻-CA 1/temporoammonic-path突触的形成，这表明了一个普遍的原则。逆行跨突触狂犬病病毒追踪显示，突触后cAMP信号传导是整个生命过程中突触持续更换所必需的。鉴于突触后亲latrophilin粘附-GPCR驱动突触形成并产生cAMP，我们认为空间限制的突触后cAMP信号在突触形成期间组织突触后特化的组装。
The localized signaling mechanisms underlying how diverse synaptic connections self-assemble into functional neural circuits during mammalian brain development remain unknown. This study develops molecular tools to target signaling perturbations to defined, nascent synaptic compartments during synapse formation. These tools reveal an essential role for compartmentalized postsynaptic cAMP signaling in driving excitatory synapse assembly. The physiological mechanisms driving synapse formation are elusive. Although numerous signals are known to regulate synapses, it remains unclear which signaling mechanisms organize initial synapse assembly. Here, we describe new tools, referred to as “SynTAMs” for synaptic targeting molecules, that enable localized perturbations of cAMP signaling in developing postsynaptic specializations. We show that locally restricted suppression of postsynaptic cAMP levels or of cAMP-dependent protein-kinase activity severely impairs excitatory synapse formation without affecting neuronal maturation, dendritic arborization, or inhibitory synapse formation. In vivo, suppression of postsynaptic cAMP signaling in CA1 neurons prevented formation of both Schaffer-collateral and entorhinal-CA1/temporoammonic-path synapses, suggesting a general principle. Retrograde trans-synaptic rabies virus tracing revealed that postsynaptic cAMP signaling is required for continuous replacement of synapses throughout life. Given that postsynaptic latrophilin adhesion-GPCRs drive synapse formation and produce cAMP, we suggest that spatially restricted postsynaptic cAMP signals organize assembly of postsynaptic specializations during synapse formation.
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