Syntaxin-3 is dispensable for basal neurotransmission and synaptic plasticity in postsynaptic hippocampal CA1 neurons

Abstract

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...

Dissociating encoding of memory and salience by manipulating long-term synaptic potentiation

“…Increasing evidence implicates a postsynaptic SNARE complex in AMPAR insertion during LTP ( 15–20 ). We previously showed that shRNA-mediated knockdown of a critical component of this postsynaptic SNARE complex, Syntaxin-3 ( Stx3 ), in CA1-region neurons impaired LTP while sparing basal synaptic transmission ( 16 , 17, but see ( 21 ) for an opposing view). In the current set of experiments, we explored whether we could use Stx3 as a molecular handle to selectively probe the role of LTP in population coding and memory formation.…”

“…An experience dependent representation likely already exists in the CA3-region. A computational model from the original publication (21) suggests that such remapping does not require CA1 specific circuitry. This upstream representation can likely be inherited even without plasticity (Fig S14).…”

Neuronal SNAP-23 scales hippocampal synaptic plasticity and memory

“…Phalloidin is known to primarily label the periodic actin lattice in dendritic spines in acute hippocampal sections (28). CaMKIIα-Cre is expressed highly in the hippocampus (23,29) as such, we consistently saw a decrease in SNAP-23 signals in the apical dendritic spines of CA1 neurons in the SNAP-23 cKO slices (Figure 1A and 1B). This decrease was also observed in the distal dendrites of the CA1 neurons (supplemental Figure 1).…”

“…This suggests that the LTP deficits are spatial learning and memory specific as demonstrated by poor Morris water maze performances, while deficits to the basal neurotransmission may affect other behaviors such as the hippocampus-dependent nestlet shredding task. The observed SNAP-23 cKO phenotypes are also different from that of syntaxin-3 cKO, as syntaxin-3 cKO led to no changes in LTP or basal neurotransmission as well as no changes in learning and memory (29). This suggests that the regulation of glutamate receptor trafficking in postsynaptic membranes are highly heterogenous, and requirements of specific SNARE proteins may depend on the neuronal activity state.…”

Pathogenic STX3 variants affecting the retinal and intestinal transcripts cause an early-onset severe retinal dystrophy in microvillus inclusion disease subjects

“…However, we cannot exclude the possibility that STX3 may be expressed in a small, specific subset of human brain cells, where it may impact human development or cognition. Early studies in mice suggested that STX3 may be involved in some types of learning and memory (Jurado et al 2013), but a subsequent study of the same brain region failed to reveal an effect of STX3 inactivation on basal synaptic function or on a specific type of synaptic plasticity or learning and memory tasks (Shi et al 2020). How might loss of STX3 function lead to photoreceptor degeneration?…”