Abstract
The impact of spontaneous neurotransmission on neuronal plasticity remains poorly understood. Here, we show that acute suppression of spontaneous NMDA receptor-mediated (NMDAR-mediated) neurotransmission potentiates synaptic responses in the CA1 regions of rat and mouse hippocampus. This potentiation requires protein synthesis, brain-derived neurotrophic factor expression, eukaryotic elongation factor-2 kinase function, and increased surface expression of AMPA receptors. Our behavioral studies link this same synaptic signaling pathway to the fast-acting antidepressant responses elicited by ketamine. We also show that selective neurotransmitter depletion from spontaneously recycling vesicles triggers synaptic potentiation via the same pathway as NMDAR blockade, demonstrating that presynaptic impairment of spontaneous release, without manipulation of evoked neurotransmission, is sufficient to elicit postsynaptic plasticity. These findings uncover an unexpectedly dynamic impact of spontaneous glutamate release on synaptic efficacy and provide new insight into a key synaptic substrate for rapid antidepressant action.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Animals
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Animals, Newborn
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Biophysics
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Brain-Derived Neurotrophic Factor / deficiency
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Electric Stimulation
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Elongation Factor 2 Kinase / deficiency
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Enzyme Inhibitors / pharmacology
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Evoked Potentials / genetics
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Evoked Potentials / physiology
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Excitatory Amino Acid Agonists / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Exploratory Behavior / drug effects
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Exploratory Behavior / physiology
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Feeding Behavior / drug effects
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Feeding Behavior / physiology
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GABA Antagonists / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Glutamic Acid / metabolism
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Hippocampus / cytology*
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Hippocampus / physiology
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In Vitro Techniques
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Inhibition, Psychological*
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Ketamine / pharmacology
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Locomotion / drug effects
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Locomotion / genetics
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Mice
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Mice, Knockout
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Neural Inhibition / drug effects
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Neural Inhibition / physiology*
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Neuronal Plasticity / physiology*
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Patch-Clamp Techniques
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Picrotoxin / pharmacology
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Rats
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Rats, Sprague-Dawley
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Receptors, AMPA / metabolism
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Sodium Channel Blockers / pharmacology
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Swimming / physiology
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Synapses / physiology*
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Synaptic Transmission / physiology*
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Tetrodotoxin / pharmacology
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Time Factors
Substances
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Brain-Derived Neurotrophic Factor
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Enzyme Inhibitors
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Excitatory Amino Acid Agonists
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Excitatory Amino Acid Antagonists
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GABA Antagonists
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Receptors, AMPA
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Sodium Channel Blockers
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Picrotoxin
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Glutamic Acid
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Tetrodotoxin
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Ketamine
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Eef2k protein, mouse
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Elongation Factor 2 Kinase