title: Acute suppression of spontaneous neurotransmission drives synaptic potentiation.
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.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9111, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Nosyreva
authors.forename: Kristen
authors.initials: K
authors.lastname: Szabla
authors.forename: Anita E
authors.initials: AE
authors.lastname: Autry
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Ryazanov
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Monteggia
authors.forename: Ege T
authors.initials: ET
authors.lastname: Kavalali
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D019208:Brain-Derived Neurotrophic Factor / Q000172:deficiency; D004558:Electric Stimulation; D054736:Elongation Factor 2 Kinase / Q000172:deficiency; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005071:Evoked Potentials / Q000235:genetics / Q000502:physiology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology* / Q000502:physiology; D066298:In Vitro Techniques; D007266:Inhibition, Psychological; D007649:Ketamine / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013550:Swimming / Q000502:physiology; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D054736:Elongation Factor 2 Kinase; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018756:GABA Antagonists; D018698:Glutamic Acid; D007649:Ketamine; D010852:Picrotoxin; D018091:Receptors, AMPA; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; C517690:Eef2k protein, mouse