title: Selective molecular impairment of spontaneous neurotransmission modulates synaptic efficacy.
abstract: Recent studies suggest that stimulus-evoked and spontaneous neurotransmitter release processes are mechanistically distinct. Here we targeted the non-canonical synaptic vesicle SNAREs Vps10p-tail-interactor-1a (vti1a) and vesicle-associated membrane protein 7 (VAMP7) to specifically inhibit spontaneous release events and probe whether these events signal independently of evoked release to the postsynaptic neuron. We found that loss of vti1a and VAMP7 impairs spontaneous high-frequency glutamate release and augments unitary event amplitudes by reducing postsynaptic eukaryotic elongation factor 2 kinase (eEF2K) activity subsequent to the reduction in N-methyl-D-aspartate receptor (NMDAR) activity. Presynaptic, but not postsynaptic, loss of vti1a and VAMP7 occludes NMDAR antagonist-induced synaptic potentiation in an intact circuit, confirming the role of these vesicular SNAREs in setting synaptic strength. Collectively, these results demonstrate that spontaneous neurotransmission signals independently of stimulus-evoked release and highlight its role as a key regulator of postsynaptic efficacy.
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Devon C
authors.identifier: 0000-0002-9354-4976
authors.initials: DC
authors.lastname: Crawford
authors.affiliation: Whole Brain Microscopy Facility, Department of Neurology and Neurotherapeutics, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Denise M O
authors.initials: DM
authors.lastname: Ramirez
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Brent
authors.initials: B
authors.lastname: Trauterman
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Monteggia
authors.affiliation: Department of Neuroscience, UT Southwestern Medical Center, Dallas, Texas 75390, USA.|Department of Physiology, UT Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Ege T
authors.initials: ET
authors.lastname: Kavalali
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D054736:Elongation Factor 2 Kinase / Q000235:genetics / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D050766:Qb-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D050766:Qb-SNARE Proteins; D050683:R-SNARE Proteins; D016194:Receptors, N-Methyl-D-Aspartate; C496926:Vamp7 protein, rat; C491417:Vti1a protein, rat; D018698:Glutamic Acid; D054736:Elongation Factor 2 Kinase