Presynaptic regulation of quantal size by the vesicular glutamate transporter VGLUT1.
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.
Department of Brain and Cognitive Sciences, Picower Center for Learning and Memory, and The Institute of Physical and Chemical Research (RIKEN), Massachusetts Institute of Technology, Cambridge, Massachusetts 02139-4307, USA.
Nathan R
NR
Wilson
Jiansheng
J
Kang
Emily V
EV
Hueske
Tony
T
Leung
Helene
H
Varoqui
Jonathan G
JG
Murnick
Jeffrey D
JD
Erickson
Guosong
G
Liu
D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D017931:DNA Primers; D005071:Evoked Potentials / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism; D006706:Homeostasis; D007091:Image Processing, Computer-Assisted; D016716:PC12 Cells; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000502:physiology*; D011789:Quantum Theory; D051381:Rats; D013569:Synapses / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000502:physiology*; D050598:Vesicular Glutamate Transport Protein 1 / Q000235:genetics / Q000502:physiology*
D017931:DNA Primers; D050598:Vesicular Glutamate Transport Protein 1; D018698:Glutamic Acid