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.

Cumulative evidence for relationships between multiple variants in the VTI1A and TCF7L2 genes and cancer incidence

“…The VTI1A gene (Gene ID: 143187) is located at ∼131 kb upstream of the TCF7L2 gene and encodes a soluble N ‐ethylmaleimide‐sensitive fusion protein‐attachment protein receptor that functions in intracellular trafficking and is involved in vesicular transport between endosomes and the trans‐Golgi network. Loss of VTI1A activity has been reported to reduce high frequency spontaneous neurotransmitter release and rapid progressive neurodegeneration in peripheral ganglia . Recently, a recurrent gene fusion connecting the first three exons of the VTI1A gene to the fourth exon of the TCF7L2 gene was found in ∼3% of colorectal carcinomas .…”

Neuronal Ca2+ signalling at rest and during spontaneous neurotransmission

“…Even during neuronal activity, it can elicit neuronal signalling that is largely independent of the biochemical pathways associated with action potential‐evoked neuronal signal transduction (Crawford et al . ; Ramirez et al . ).…”

Regulation of synaptic scaling by action potential–independent miniature neurotransmission

“…This idea was consistent with the possibility that reducing spontaneous glutamatergic release alone (without changes in evoked release or spiking) could trigger scaling. It has now been demonstrated in two recent reports that AMPAergic upward scaling can be triggered by specifically reducing the frequency of glutamate spontaneous release, while leaving evoked release intact (Crawford, Ramirez, Trauterman, Monteggia, & Kavalali, ; Ramirez et al, ). These studies used a genetic knockdown strategy where the expression of two different sets of synaptic vesicle proteins (VAMP7/vti1a or Doc2‐like protein family) were reduced selectively, lowering mEPSC frequency for days and triggering an upward scaling.…”