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Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors.

Examining the behavioral consequences of selective CNS neuronal activation is a powerful tool for elucidating mammalian brain function in health and disease. Newly developed genetic, pharmacological, and optical tools allow activation of neurons with exquisite spatiotemporal resolution; however, the inaccessibility to light of widely distributed neuronal populations and the invasiveness required for activation by light or infused ligands limit the utility of these methods. To overcome these barriers, we created transgenic mice expressing an evolved G protein-coupled receptor (hM3Dq) selectively activated by the pharmacologically inert, orally bioavailable drug clozapine-N-oxide (CNO). Here, we expressed hM3Dq in forebrain principal neurons. Local field potential and single-neuron recordings revealed that peripheral administration of CNO activated hippocampal neurons selectively in hM3Dq-expressing mice. Behavioral correlates of neuronal activation included increased locomotion, stereotypy, and limbic seizures. These results demonstrate a powerful chemical-genetic tool for remotely controlling the activity of discrete populations of neurons in vivo.

Pubmed ID: 19607790

Authors

  • Alexander GM
  • Rogan SC
  • Abbas AI
  • Armbruster BN
  • Pei Y
  • Allen JA
  • Nonneman RJ
  • Hartmann J
  • Moy SS
  • Nicolelis MA
  • McNamara JO
  • Roth BL

Journal

Neuron

Publication Data

July 16, 2009

Associated Grants

  • Agency: NIGMS NIH HHS, Id: GM007250
  • Agency: NIGMS NIH HHS, Id: GM008719
  • Agency: NIGMS NIH HHS, Id: GM07040-34
  • Agency: NIGMS NIH HHS, Id: GM074554
  • Agency: NICHD NIH HHS, Id: HD03110
  • Agency: NICHD NIH HHS, Id: HD040127
  • Agency: NIMH NIH HHS, Id: MH082441-02
  • Agency: NINDS NIH HHS, Id: NS049534
  • Agency: NINDS NIH HHS, Id: NS056217
  • Agency: NINDS NIH HHS, Id: NS060326
  • Agency: NINDS NIH HHS, Id: R01 NS056217
  • Agency: NINDS NIH HHS, Id: R01 NS056217-03
  • Agency: NINDS NIH HHS, Id: R01 NS056217-04
  • Agency: NINDS NIH HHS, Id: R33 NS049534
  • Agency: NINDS NIH HHS, Id: R33 NS049534-04
  • Agency: NIMH NIH HHS, Id: U19 MH082441

Mesh Terms

  • Animals
  • Behavior, Animal
  • Brain
  • Clozapine
  • Dose-Response Relationship, Drug
  • Doxycycline
  • Evoked Potentials
  • Evolution, Molecular
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Gene Expression
  • Hippocampus
  • Humans
  • In Vitro Techniques
  • Locomotion
  • Membrane Potentials
  • Mice
  • Mice, Transgenic
  • Neurons
  • Patch-Clamp Techniques
  • Receptors, G-Protein-Coupled
  • Stereotyped Behavior
  • Time Factors