Assembly of SNARE complexes that mediate neurotransmitter release requires opening of a ‘closed’ conformation of UNC-64/syntaxin. Rescue of unc-13/Munc13 mutant phenotypes by overexpressed open UNC-64/syntaxin suggested a specific function of UNC-13/Munc13 in opening UNC-64/ syntaxin. Here, we revisit the effects of open unc-64/syntaxin by generating knockin (KI) worms. The KI animals exhibit enhanced spontaneous and evoked exocytosis compared to WT animals. Unexpectedly, the open syntaxin KI partially suppresses exocytosis defects of various mutants, including snt-1/synaptotagmin, unc-2/P/Q/N-type Ca2+ channel alpha-subunit and unc-31/CAPS, in addition to unc-13/Munc13 and unc-10/RIM, and enhanced exocytosis in tom-1/Tomosyn mutants. However, open syntaxin aggravates the defects of unc-18/Munc18 mutants. Correspondingly, open syntaxin partially bypasses the requirement of Munc13 but not Munc18 for liposome fusion. Our results show that facilitating opening of syntaxin enhances exocytosis in a wide range of genetic backgrounds, and may provide a general means to enhance synaptic transmission in normal and disease states.

Recent evidence suggests that SNARE fusion machinery play critical roles in postsynaptic neurotransmitter receptor trafficking, which is essential for synaptic plasticity. However, the key SNAREs involved remain highly controversial; syntaxin-3 and syntaxin-4 are leading candidates for the syntaxin isoform underlying postsynaptic plasticity. In a previous study, we showed that pyramidalneuron specific conditional knockout (cKO) of syntaxin-4 significantly reduces basal transmission, synaptic plasticity and impairs postsynaptic receptor trafficking. However, this does not exclude a role for syntaxin-3 in such processes. Here, we generated and analyzed syntaxin-3 cKO mice. Extracellular field recordings in hippocampal slices showed that syntaxin-3 cKO did not exhibit significant changes in CA1 basal neurotransmission or in paired-pulse ratios. Importantly, there were no observed differences during LTP in comparison to control mice. Syntaxin-3 cKO mice performed similarly as the controls in spatial and contextual learning tasks. Consistent with the minimal effects of syntaxin-3 cKO, syntaxin-3 mRNA level was very low in hippocampal and cortex pyramidal neurons, but strongly expressed in the corpus callosum and caudate axon fibers. Together, our data suggest that syntaxin-3 is dispensable for hippocampal basal neurotransmission and synaptic plasticity, and further supports the notion that syntaxin-4 is the major isoform mediating these processes.Synaptic transmission is essential for neuronal communication in the brain. During synaptic transmission, presynaptic neurons release neurotransmitters that bind to their respective receptors on the postsynaptic membrane. Ionotropic glutamate receptors (AMPARs and NMDARs) and GABA receptors on the postsynaptic membrane undergo receptor recycling. Receptor recycling is an essential process in synaptic plasticity such as long-term potentiation (LTP). LTP is a cellular correlate for higher-level cognitive functions of learning and memory 1-5 and requires rapid modifications in the quantity and composition of postsynaptic glutamate receptors 4,6,7 . Despite its importance, the underlying mechanisms of postsynaptic membrane receptor trafficking still remain unclear.Postsynaptic receptor trafficking employs a unique soluble NSF-attachment protein receptor (SNARE) complex that mediates the attachment and fusion of vesicles containing postsynaptic receptors to target membranes. The SNARE complex is composed of one vesicle membrane protein (v-SNARE; synaptobrevin) and two target membrane proteins (t-SNAREs; syntaxin and SNAP-25 isoforms) 8 . Botulinum neurotoxin B (BoNT/B) proteolyzes synaptobrevin-2 and when injected into CA1 pyramidal cells, blocks LTP induction 9 . This suggests that this open Scientific RepoRtS | (2020) 10:709 | https://doi.org/10.1038/s41598-019-57388-6www.nature.com/scientificreports www.nature.com/scientificreports/ v-SNARE is imperative for AMPAR delivery to the postsynaptic membrane during LTP. However, the particular isoforms of t-SNAREs involved in postsyna...

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