title: 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.
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Brenda C
authors.identifier: 0000-0001-9036-2686
authors.initials: BC
authors.lastname: Shields
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Elizabeth
authors.identifier: 0000-0003-0170-3237
authors.initials: E
authors.lastname: Kahuno
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Charles
authors.identifier: 0000-0002-6785-7741
authors.initials: C
authors.lastname: Kim
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Pierre F
authors.identifier: 0000-0001-5617-4171
authors.initials: PF
authors.lastname: Apostolides
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Jennifer
authors.identifier: 0000-0001-7090-4409
authors.initials: J
authors.lastname: Brown
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Sarah
authors.identifier: 0000-0001-5682-201X
authors.initials: S
authors.lastname: Lindo
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Brett D
authors.identifier: 0000-0003-2288-054X
authors.initials: BD
authors.lastname: Mensh
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Joshua T
authors.identifier: 0000-0002-4436-1057
authors.initials: JT
authors.lastname: Dudman
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA.
authors.forename: Luke D
authors.identifier: 0000-0002-0789-6343
authors.initials: LD
authors.lastname: Lavis
authors.affiliation: Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. michael.tadross@duke.edu.|Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA.
authors.forename: Michael R
authors.identifier: 0000-0002-7752-6380
authors.initials: MR
authors.lastname: Tadross
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects; D004195:Disease Models, Animal; D015195:Drug Design; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D017774:Long-Term Potentiation / Q000187:drug effects; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects; D062308:Optogenetics; D010300:Parkinson Disease / Q000503:physiopathology; D011810:Quinoxalines / Q000494:pharmacology*; D017470:Receptors, Glutamate / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D011810:Quinoxalines; D017470:Receptors, Glutamate; C086162:6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione