Novel Ca2+-dependent mechanisms regulate spontaneous release at excitatory synapses onto CA1 pyramidal cells

Although long thought to simply be a source of synaptic noise, spontaneous, action potential-independent release of neurotransmitter from presynaptic terminals has multiple roles in synaptic function. We explored whether and to what extent the two predominantly proposed mechanisms for explaining spontaneous release, stochastic activation of voltage-gated Ca 2+ channels (VGCCs) or activation of Ca 2+ -sensing receptors (CaSRs) by extracellular Ca 2+ , played a role in the sensitivity of spontaneous release to the level of extracellular Ca 2+ concentration at excitatory synapses at CA1 pyramidal cells of the adult male mouse hippocampus. Blocking VGCCs with Cd 2+ had no effect on spontaneous release, ruling out stochastic activation of VGCCs. Although divalent cation agonists of CaSRs, Co 2+ and Mg 2+ , dramatically enhanced miniature excitatory postsynaptic current (mEPSC) frequency, potent positive and negative allosteric modulators of CaSRs had no effect. Moreover, immunoblot analysis of hippocampal lysates failed to detect CaSR expression, ruling out the CaSR. Instead, the increase in mEPSC frequency induced by Co 2+ and Mg 2+ was mimicked by lowering postsynaptic Ca 2+ levels with BAPTA. Together, our results suggest that a reduction in intracellular Ca 2+ may trigger a homeostatic-like compensatory response that upregulates spontaneous transmission at excitatory synapses onto CA1 pyramidal cells in the adult hippocampus. NEW & NOTEWORTHY We show that the predominant theories for explaining the regulation of spontaneous, action potential-independent synaptic release do not explain the sensitivity of this type of synaptic transmission to external Ca 2+ concentration at excitatory synapses onto hippocampal CA1 pyramidal cells. In addition, our data indicate that intracellular Ca 2+ levels in CA1 pyramidal cells regulate spontaneous release, suggesting that excitatory synapses onto CA1 pyramidal cells may express a novel, rapid form of homeostatic plasticity.