Deconstructing behavioral neuropharmacology with cellular specificity
Abstract
Behavior has molecular, cellular, and circuit determinants. However, because many proteins are broadly expressed, their acute manipulation within defined cells has been difficult. Here, we combined the speed and molecular specificity of pharmacology with the cell type specificity of genetic tools. DART (drugs acutely restricted by tethering) is a technique that rapidly localizes drugs to the surface of defined cells, without prior modification of the native target. We first developed an AMPAR antagonist DART, with validation in cultured neuronal assays, in slices of mouse dorsal striatum, and in behaving mice. In parkinsonian animals, motor deficits were causally attributed to AMPARs in indirect spiny projection neurons (iSPNs) and to excess phasic firing of tonically active interneurons (TANs). Together, iSPNs and TANs (i.e., D2 cells) drove akinesia, whereas movement execution deficits reflected the ratio of AMPARs in D2 versus D1 cells. Finally, we designed a muscarinic antagonist DART in one iteration, demonstrating applicability of the method to diverse targets.
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This produces an approximately 100-fold enrichment of the drug on the surface of HaloTag-expressing cells.
“A protein called HaloTag is expressed in defined neuronal cells (e.g. using a cell-type-specific promoter) and captures and tethers drugs to the cell surface over seconds to minutes, producing an approximately 100-fold enrichment of the drug on the surface of the HaloTag-expressing cells.”
From An emerging circuit pharmacology of GABAA receptors (2018) · cites this paper as [143]
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Next-generation interfaces for studying neural function
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- Authors
- Shields, B. C., Kahuno, E., Kim, C., Apostolides, P. F., Brown, J., Lindo, S., Mensh, B. D., Dudman, J. T., Lavis, L. D., & Tadross, M. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Shields, Brenda C.
- Kahuno, Elizabeth
- Kim, Charles
- Apostolides, Pierre F.
- Tadross, Michael R.
- ORCID
- Venue
- Science
- Published
- 2017-04-07
- Volume
- 356
- Issue
- 6333
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2604969293
- Cited by
- 135
- References
- 77
- Citations by year
- 2026: 14 · 2025: 13 · 2024: 14 · 2023: 11 · 2022: 17 · 2021: 11 · 2020: 13 · 2019: 18 · 2018: 15 · 2017: 9
- FWCI
- 7.36
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Howard Hughes Medical Institute (award300683)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Neurology › Neurological disorders and treatments
- Keywords
- DART, AMPA receptor antagonism, antimuscarinic agents, dorsal striatum, dopamine D2 receptor, dopamine D1 receptor, parkinsonism, akinesia, motor impairment, striatal circuitry
- MeSH terms
- Animals, Behavior, Animal, Corpus Striatum, Disease Models, Animal, Neurons, Parkinson Disease, Quinoxalines, Drug Design, Receptors, Glutamate, Long-Term Potentiation, Excitatory Amino Acid Antagonists, Muscarinic Antagonists, Mice, Optogenetics
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