Abstract
The brain's endocannabinoid retrograde messenger system decreases presynaptic transmitter release, but its physiological function is uncertain. We show that endocannabinoid signaling is absent when spatially dispersed synapses are activated on rodent cerebellar Purkinje cells but that it reduces presynaptic glutamate release when nearby synapses are active. This switching of signaling according to the spatial pattern of activity is controlled by postsynaptic type I metabotropic glutamate receptors, which are activated disproportionately when glutamate spillover between synapses produces synaptic crosstalk. When spatially distributed synapses are activated, endocannabinoid inhibition of transmitter release can be rescued by inhibiting glutamate uptake to increase glutamate spillover. Endocannabinoid signaling initiated by type I metabotropic glutamate receptors is a homeostatic mechanism that detects synaptic crosstalk and downregulates glutamate release in order to promote synaptic independence.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cannabinoid Receptor Antagonists
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Cannabinoid Receptor Modulators / metabolism*
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Cannabinoid Receptor Modulators / pharmacology
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Cerebellar Cortex / drug effects
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Cerebellar Cortex / metabolism*
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Down-Regulation / drug effects
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Down-Regulation / physiology
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Endocannabinoids*
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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Glutamic Acid / metabolism
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Homeostasis / drug effects
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Homeostasis / physiology
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Male
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Mice
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Neural Inhibition / drug effects
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Neural Inhibition / physiology
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Neural Pathways / drug effects
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Neural Pathways / metabolism
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Organ Culture Techniques
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Patch-Clamp Techniques
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Presynaptic Terminals / drug effects
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Presynaptic Terminals / metabolism
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Purkinje Cells / drug effects
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Purkinje Cells / metabolism*
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Rats
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Receptors, Cannabinoid / metabolism
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Receptors, Metabotropic Glutamate / agonists
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Receptors, Metabotropic Glutamate / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Synapses / drug effects
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Synapses / metabolism*
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology*
Substances
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Cannabinoid Receptor Antagonists
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Cannabinoid Receptor Modulators
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Endocannabinoids
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Excitatory Amino Acid Agonists
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Receptors, Cannabinoid
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Receptors, Metabotropic Glutamate
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metabotropic glutamate receptor type 1
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Glutamic Acid