@article {64840, title = {Ultrapotent chemogenetics for research and potential clinical applications.}, journal = {Science}, volume = {364}, year = {2019}, month = {2019 Mar 14}, pages = {eaav5282}, abstract = {

Chemogenetics enables non-invasive chemical control over cell populations in behaving animals. However, existing small molecule agonists show insufficient potency or selectivity. There is also need for chemogenetic systems compatible with both research and human therapeutic applications. We developed a new ion channel-based platform for cell activation and silencing that is controlled by low doses of the anti-smoking drug varenicline. We then synthesized novel sub-nanomolar potency agonists, called uPSEMs, with high selectivity for the chemogenetic receptors. uPSEMs and their receptors were characterized in brains of mice and a rhesus monkey by in vivo electrophysiology, calcium imaging, positron emission tomography, behavioral efficacy testing, and receptor counterscreening. This platform of receptors and selective ultrapotent agonists enables potential research and clinical applications of chemogenetics.

}, issn = {1095-9203}, doi = {10.1126/science.aav5282}, author = {Magnus, Christopher J and Lee, Peter H and Bonaventura, Jordi and Zemla, Roland and Gomez, Juan L and Ramirez, Melissa H and Hu, Xing and Galvan, Adriana and Basu, Jayeeta and Michaelides, Michael and Sternson, Scott M} } @article {4594, title = {Regulation of neuronal input transformations by tunable dendritic inhibition.}, journal = {Nature Neuroscience}, volume = {15}, year = {2012}, month = {2012 Jan 15}, pages = {423-30}, abstract = {

Transforming synaptic input into action potential output is a fundamental function of neurons. The pattern of action potential output from principal cells of the mammalian hippocampus encodes spatial and nonspatial information, but the cellular and circuit mechanisms by which neurons transform their synaptic input into a given output are unknown. Using a combination of optical activation and cell type-specific pharmacogenetic silencing in vitro, we found that dendritic inhibition is the primary regulator of input-output transformations in mouse hippocampal CA1 pyramidal cells, and acts by gating the dendritic electrogenesis driving burst spiking. Dendrite-targeting interneurons are themselves modulated by interneurons targeting pyramidal cell somata, providing a synaptic substrate for tuning pyramidal cell output through interactions in the local inhibitory network. These results provide evidence for a division of labor in cortical circuits, where distinct computational functions are implemented by subtypes of local inhibitory neurons.

}, issn = {1546-1726}, doi = {10.1038/nn.3024}, author = {Lovett-Barron, Matthew and Turi, Gergely F and Kaifosh, Patrick and Lee, Peter H and Bolze, Fr{\'e}d{\'e}ric and Sun, Xiao-Hua and Nicoud, Jean-Fran\c cois and Zemelman, Boris V and Sternson, Scott M and Losonczy, Attila} } @article {3977, title = {Chemical and genetic engineering of selective ion channel-ligand interactions.}, journal = {Science}, volume = {333}, year = {2011}, month = {2011 Sep 2}, pages = {1292-6}, abstract = {

Ionic flux mediates essential physiological and behavioral functions in defined cell populations. Cell type-specific activators of diverse ionic conductances are needed for probing these effects. We combined chemistry and protein engineering to enable the systematic creation of a toolbox of ligand-gated ion channels (LGICs) with orthogonal pharmacologic selectivity and divergent functional properties. The LGICs and their small-molecule effectors were able to activate a range of ionic conductances in genetically specified cell types. LGICs constructed for neuronal perturbation could be used to selectively manipulate neuron activity in mammalian brains in vivo. The diversity of ion channel tools accessible from this approach will be useful for examining the relationship between neuronal activity and animal behavior, as well as for cell biological and physiological applications requiring chemical control of ion conductance.

}, keywords = {5-HT3, Animals, Benzamides, Bicyclo Compounds, Brain, Feeding Behavior, Female, Glycine, HEK293 Cells, Humans, Inbred C57BL, Ion Channel Gating, Ligand-Gated Ion Channels, Ligands, Membrane Potentials, Mice, Mutagenesis, Neurons, Nicotinic, Patch-Clamp Techniques, Protein Binding, Protein Engineering, Protein Structure, Quinuclidines, Receptors, Recombinant Fusion Proteins, Serotonin, Small Molecule Libraries, Stereoisomerism, Tertiary}, issn = {1095-9203}, doi = {10.1126/science.1206606}, author = {Magnus, Christopher J and Lee, Peter H and Atasoy, Deniz and Su, Helen H and Looger, Loren L and Sternson, Scott M} }