Presynaptic Regulation of Quantal Size by the Vesicular Glutamate Transporter VGLUT1

Abstract

A fundamental question in synaptic physiology is whether the unitary strength of a synapse can be regulated by presynaptic characteristics and, if so, what those characteristics might be. Here, we characterize a newly proposed mechanism for altering the strength of glutamatergic synapses based on the recently identified vesicular glutamate transporter VGLUT1. We provide direct evidence that filling in isolated synaptic vesicles is subject to a dynamic equilibrium that is determined by both the concentration of available glutamate and the number of vesicular transporters participating in loading. We observe that changing the number of vesicular transporters expressed at hippocampal excitatory synapses results in enhanced evoked and miniature responses and verify biophysically that these changes correspond to an increase in the amount of glutamate released per vesicle into the synaptic cleft. In addition, we find that this modulation of synaptic strength by vesicular transporter expression is endogenously regulated, both across development to coincide with a maturational increase in vesicle cycling and quantal amplitude and by excitatory and inhibitory receptor activation in mature neurons to provide an activity-dependent scaling of quantal size via a presynaptic mechanism. Together, these findings underscore that vesicular transporter expression is used endogenously to directly regulate the extent of glutamate release, providing a concise presynaptic mechanism for controlling the quantal efficacy of excitatory transmission during synaptic refinement and plasticity.

Increased Vulnerability to Depressive-Like Behavior of Mice with Decreased Expression of VGLUT1

“…Previous studies show that VGLUT1 is the major isoform in both the frontal cortex and the hippocampus (30,31), where it plays a key role in the vesicular uptake and synaptic transmission of glutamate (13)(14)(15)(16). The downregulation of cortical and hippocampal EAAT1 supports the idea of decreased glutamate release in the VGLUT1 dependent synapses because this glial transporter is regulated by the amount of glutamate released into the synaptic cleft (32,33).…”

“…At the experimental level, the vesicular glutamate transporter 1 (VGLUT1) has been reported to play a key role in the synaptic release (12) and the efficacy of glutamatergic synaptic transmission (13)(14)(15)(16). A recent study carried out in our laboratory reports that mice heterozygous for VGLUT1 (VGLUT1+/-), exhibit decreased cortical and hippocampal levels (35-45 %) of the inhibitory neurotransmitter GABA as well as helplessness in the forced swimming test (17).…”

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

“…However, we also found that the excitatory synapses remaining after pruning have higher apparent levels of VGlut1 and PSD95 proteins. Higher levels of VGlut1 and PSD95 have been shown to increase the amplitude of excitatory postsynaptic currents and to correlate with the maturation of excitatory synapses (45,46). Consequently, the excitatory synapses on PV interneurons that remain after pruning likely represent mature synaptic connections with stronger excitatory neurotransmission.…”

Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats

“…Repeated treatment with morphine induces a significant increase in the protein levels of membrane-bound GLT1 [40]. The increasing expression of GLT1 directly promotes glutamate reuptake and decreases extracellular glutamate concentrations [41]. Although glial GLT1 was thought to be primarily responsible for extracellular glutamate reuptake in most brain regions in drug addiction, Xu et al reported that neuronal GLT1 contributes to hippocampal glutamate reuptake during morphine withdrawal [40].…”