Rapid and reversible chemical inactivation of synaptic transmission in genetically targeted neurons.
Inducible and reversible silencing of selected neurons in vivo is critical to understanding the structure and dynamics of brain circuits. We have developed Molecules for Inactivation of Synaptic Transmission (MISTs) that can be genetically targeted to allow the reversible inactivation of neurotransmitter release. MISTs consist of modified presynaptic proteins that interfere with the synaptic vesicle cycle when crosslinked by small molecule "dimerizers." MISTs based on the vesicle proteins VAMP2/Synaptobrevin and Synaptophysin induced rapid ( approximately 10 min) and reversible block of synaptic transmission in cultured neurons and brain slices. In transgenic mice expressing MISTs selectively in Purkinje neurons, administration of dimerizer reduced learning and performance of the rotarod behavior. MISTs allow for specific, inducible, and reversible lesions in neuronal circuits and may provide treatment of disorders associated with neuronal hyperactivity.
Karpova
Alla Y
AY
Howard Hughes Medical Institute, USA.
Tervo
Dougal G R
DG
Gray
Noah W
NW
Svoboda
Karel
K
D000818:Animals; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000494:pharmacology; D019281:Dimerization; D018390:Gene Targeting; D066298:In Vitro Techniques; D007858:Learning / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000378:metabolism; D011689:Purkinje Cells / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism; D016708:Synaptophysin / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013997:Time Factors; D050988:Vesicle-Associated Membrane Protein 2 / Q000187:drug effects / Q000235:genetics / Q000502:physiology
D003432:Cross-Linking Reagents; D018377:Neurotransmitter Agents; D016708:Synaptophysin; D050988:Vesicle-Associated Membrane Protein 2