The relationship between glutamate dynamics and activity-dependent synaptic plasticity

Abstract

The spatiotemporal dynamics of excitatory neurotransmission must be tightly regulated to achieve efficient synaptic communication. By limiting spillover, glutamate transporters are believed to prevent excessive activation of extrasynaptically located receptors that can impair synaptic plasticity. While glutamate transporter expression is reduced in numerous neurodegenerative diseases, the contributions of transporter dysfunction to disease pathophysiology remain ambiguous as the fundamental relationship between glutamate dynamics and plasticity, and the mechanisms linking these two phenomena, remain poorly understood. Here, we combined electrophysiology and real-time high-speed imaging of extracellular glutamate transients during LTP induction and characterized the sensitivity of the relationship between glutamate dynamics during theta burst stimulation (TBS) and the resulting magnitude of LTP consolidation, both in control conditions and following selective and nonselective glutamate transporter blockade. Glutamate clearance times were negatively correlated with LTP magnitude following nonselective glutamate transporter inhibition but not following selective blockade of a majority of GLT-1, the brain’s most abundant glutamate transporter. Although glutamate transporter inhibition reduced the postsynaptic population response to TBS, calcium responses to TBS were greatly exaggerated. The source of excess calcium was dependent on NMDARs, L-type VGCCs, GluA2-lacking AMPARs, and internal calcium stores. Surprisingly, inhibition of L-type VGCCs, but not GluA2-lacking AMPARs or ryanodine receptors, was required to restore robust LTP. In all, these data provide a detailed understanding of the relationship between glutamate dynamics and plasticity and uncover important mechanisms by which poor glutamate uptake can negatively impact LTP consolidation.