2024年6月14日出版的《自然—方法学》杂志发表了美国杜克大学Michael R. Tadross研究组的最新成果，他们开发了DART.2——具有千倍细胞特异性的双向突触药理学分析工具。

精准药理学旨在揭示复杂组织中的特定细胞相互作用。为了实现精准药理学的宗旨，研究人员推出了第二代细胞特异性药理学技术DART.2（系留药物急性限制）。该技术的核心改进是优化了细胞特异性，即使是致痫药物的靶向给药也不会产生脱靶效应，并将细胞特异性在15分钟内提高了3000倍。

此外，研究还介绍了全脑给药方法，以替代局部插管和全脑剂量定量的示踪试剂。研究人员阐述了四种药物-两种可以拮抗兴奋性和抑制性突触后受体，两种可实现异位增效这些受体。它们的多功能性在小鼠的多个脑区得到了验证，包括小脑、纹状体、视觉皮层和视网膜。

最后，在腹侧被盖区，研究人员发现阻断多巴胺神经元的抑制性输入会加速运动，这与之前的光遗传学和药理学研究结果形成鲜明对比。除了能对化学突触进行双向扰动外，这些试剂还能在基因特异性突触后细胞，和介导神经递质传递的突触前细胞之间，提供交叉精度。

附：英文原文

Title: DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity

Author: Shields, Brenda C., Yan, Haidun, Lim, Shaun S. X., Burwell, Sasha C. V., Cammarata, Celine M., Fleming, Elizabeth A., Yousefzadeh, S. Aryana, Goldenshtein, Victoria Z., Kahuno, Elizabeth W., Vagadia, Purav P., Loughran, Marie H., Zhiquan, Lei, McDonnell, Mark E., Scalabrino, Miranda L., Thapa, Mishek, Hawley, Tammy M., Field, Greg D., Hull, Court, Schiltz, Gary E., Glickfeld, Lindsey L., Reitz, Allen B., Tadross, Michael R.

Issue&Volume: 2024-06-14

Abstract: Precision pharmacology aims to manipulate specific cellular interactions within complex tissues. In this pursuit, we introduce DART.2 (drug acutely restricted by tethering), a second-generation cell-specific pharmacology technology. The core advance is optimized cellular specificity—up to 3,000-fold in 15min—enabling the targeted delivery of even epileptogenic drugs without off-target effects. Additionally, we introduce brain-wide dosing methods as an alternative to local cannulation and tracer reagents for brain-wide dose quantification. We describe four pharmaceuticals—two that antagonize excitatory and inhibitory postsynaptic receptors, and two that allosterically potentiate these receptors. Their versatility is showcased across multiple mouse-brain regions, including cerebellum, striatum, visual cortex and retina. Finally, in the ventral tegmental area, we find that blocking inhibitory inputs to dopamine neurons accelerates locomotion, contrasting with previous optogenetic and pharmacological findings. Beyond enabling the bidirectional perturbation of chemical synapses, these reagents offer intersectional precision—between genetically defined postsynaptic cells and neurotransmitter-defined presynaptic partners.

DOI: 10.1038/s41592-024-02292-9

Source: https://www.nature.com/articles/s41592-024-02292-9