Shields et al. DART.2: bidirectional synaptic pharmacology with thousandfold cellular specificity. Nature Methods, 2024. 21, 1288–1297. https://doi.org/10.1038/s41592-024-02292-9
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.