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DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity. Nat Methods 2024 Jul;21(7):1288-1297

Date

06/15/2024

Pubmed ID

38877316

Pubmed Central ID

PMC11569460

DOI

10.1038/s41592-024-02292-9

Scopus 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 MR

Author

Miranda L. Scalabrino PhD Assistant Professor in the Ophthalmology and Visual Sciences department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Brain
Dopaminergic Neurons
Female
Humans
Male
Mice
Mice, Inbred C57BL
Synapses