Recombinase-Dependent Mouse Lines for Chemogenetic Activation of Genetically Defined Cell Types.
Chemogenetic technologies, including the mutated human Gq-coupled M3 muscarinic receptor (hM3Dq), have greatly facilitated our ability to directly link changes in cellular activity to altered physiology and behavior. Here, we extend the hM3Dq toolkit with recombinase-responsive mouse lines that permit hM3Dq expression in virtually any cell type. These alleles encode a fusion protein designed to increase effective expression levels by concentrating hM3Dq to the cell body and dendrites. To illustrate their broad utility, we targeted three different genetically defined cell populations: noradrenergic neurons of the compact, bilateral locus coeruleus and two dispersed populations, Camk2a+ neurons and GFAP+ glia. In all three populations, we observed reproducible expression and confirmed that activation of hM3Dq is sufficient to dose-dependently evoke phenotypic changes, without extreme phenotypes associated with hM3Dq overexpression. These alleles offer the ability to non-invasively control activity of diverse cell types to uncover their function and dysfunction at any developmental stage.
Neurobiology Laboratory, Department of Health and Human Services, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC 27709, USA.
Natale R
NR
Sciolino
Neurobiology Laboratory, Department of Health and Human Services, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC 27709, USA.
Nicholas W
NW
Plummer
Neurobiology Laboratory, Department of Health and Human Services, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC 27709, USA.
Yu-Wei
YW
Chen
Neurobiology Laboratory, Department of Health and Human Services, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC 27709, USA.
Georgia M
GM
Alexander
Biotechnology Program, Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27695, USA.
Sabrina D
SD
Robertson
Neurobiology Laboratory, Department of Health and Human Services, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC 27709, USA.
Serena M
SM
Dudek
Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA; Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC 27514, USA.
Zoe A
ZA
McElligott
Neurobiology Laboratory, Department of Health and Human Services, National Institute of Environmental Health Sciences (NIEHS), NIH, Research Triangle Park, NC 27709, USA. Electronic address: patricia.jensen@nih.gov.
Patricia
P
Jensen
D000483:Alleles; D000818:Animals; D001007:Anxiety / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D015198:Designer Drugs / Q000494:pharmacology*; D065818:Gamma Rhythm / Q000187:drug effects; D005821:Genetic Techniques; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007035:Hypothermia / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D019426:Integrases / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics
D015198:Designer Drugs; D043587:Receptor, Muscarinic M3; C045073:Cre recombinase; D019426:Integrases; D003024:Clozapine