Neuron
Volume 82, Issue 4, 21 May 2014, Pages 797-808
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Chemogenetic Synaptic Silencing of Neural Circuits Localizes a Hypothalamus→Midbrain Pathway for Feeding Behavior

https://doi.org/10.1016/j.neuron.2014.04.008Get rights and content
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Highlights

  • hM4D and CNO inhibit synaptic transmission cell-type selectively

  • hM4Dnrxn suppresses synaptic release probability without altering somatic conductance

  • In vivo synaptic silencing shows ±500 μm precision using intracranial CNO injection

  • hM4Dnrxn/CNO identifies a feeding circuit from paraventricular hypothalamus→midbrain

Summary

Brain function is mediated by neural circuit connectivity, and elucidating the role of connections is aided by techniques to block their output. We developed cell-type-selective, reversible synaptic inhibition tools for mammalian neural circuits by leveraging G protein signaling pathways to suppress synaptic vesicle release. Here, we find that the pharmacologically selective designer Gi-protein-coupled receptor hM4D is a presynaptic silencer in the presence of its cognate ligand clozapine-N-oxide (CNO). Activation of hM4D signaling sharply reduced synaptic release probability and synaptic current amplitude. To demonstrate the utility of this tool for neural circuit perturbations, we developed an axon-selective hM4D-neurexin variant and used spatially targeted intracranial CNO injections to localize circuit connections from the hypothalamus to the midbrain responsible for feeding behavior. This synaptic silencing approach is broadly applicable for cell-type-specific and axon projection-selective functional analysis of diverse neural circuits.

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