DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity. Nat Methods 2024 Jul;21(7):1288-1297
Date
06/15/2024Pubmed ID
38877316Pubmed Central ID
PMC11569460DOI
10.1038/s41592-024-02292-9Scopus ID
2-s2.0-85195969411 (requires institutional sign-in at Scopus site)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 15 min-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.
Author List
Shields BC, Yan H, Lim SSX, Burwell SCV, Cammarata CM, Fleming EA, Yousefzadeh SA, Goldenshtein VZ, Kahuno EW, Vagadia PP, Loughran MH, Zhiquan L, McDonnell ME, Scalabrino ML, Thapa M, Hawley TM, Field GD, Hull C, Schiltz GE, Glickfeld LL, Reitz AB, Tadross MRAuthor
Miranda L. Scalabrino PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBrain
Dopaminergic Neurons
Female
Humans
Male
Mice
Mice, Inbred C57BL
Synapses
