Nonlinear [Ca ] Signaling in Dendrites and Spines Caused by Activity-Dependent Depression of Ca Extrusion

Spine Ca 2 triggers the induction of synaptic plasticity and other adaptive neuronal responses. The amplitude and time course of Ca 2 signals specify the activation of the signaling pathways that trigger different forms of plasticity such as long-term potentiation and depression. The shapes of Ca 2 signals are determined by the dynamics of Ca 2 sources, Ca 2 buffers, and Ca 2 extrusion mechanisms. Here we show in rat CA1 pyramidal neurons that plasma membrane Ca 2 pumps (PMCAs) and Na /Ca 2 exchangers are the major Ca 2 extrusion pathways in spines and small dendrites. Surprisingly, we found that Ca 2 extrusion via PMCA and Na /Ca 2 exchangers slows in an activity-dependent manner, mediated by intracellular Na and Ca 2 accumulations. This activity-dependent depression of Ca 2 extrusion is, in part, attributable to Ca 2 -dependent inactivation of PMCAs. Ca 2 extrusion recovers from depression with a time constant of 0.5 s. Depression of Ca 2 extrusion provides a positive feedback loop, converting small differences in stimuli into large differences in Ca 2 concentration. Depression of Ca 2 extrusion produces Ca 2 concentration dynamics that depend on the history of neuronal activity and therefore likely modulates the induction of synaptic plasticity.