Extracellular Ca²⁺ Depletion Contributes to Fast Activity-Dependent Modulation of Synaptic Transmission in the Brain

Abstract

Synaptic activation is associated with rapid changes in intracellular Ca²⁺, while the extracellular Ca²⁺ level is generally assumed to be constant. Here, using a novel optical method to measure changes in extracellular Ca²⁺ at high spatial and temporal resolution, we find that brief trains of synaptic transmission in hippocampal area CA1 induce transient depletion of extracellular Ca²⁺. We show that this depletion, which depends on postsynaptic NMDA receptor activation, decreases the Ca²⁺ available to enter individual presynaptic boutons of CA3 pyramidal cells. This in turn reduces the probability of consecutive synaptic releases at CA3−CA1 synapses and therefore contributes to short-term paired-pulse depression of minimal responses. This activity-dependent depletion of extracellular Ca²⁺ represents a novel form of fast retrograde synaptic signaling that can modulate glutamatergic information transfer in the brain.