The Na+/Ca2+exchangers NCX1, NCX2, and NCX3 are vital for the control of cellular Ca2+homeostasis. Here, we show that a doublet of downstream regulatory element sites in the promoter of theNCX3gene mediates transcriptional repression of NCX3 by the Ca2+-modulated transcriptional repressor downstream regulatory element antagonist modulator (DREAM). Overexpression of a DREAM EF-hand mutant insensitive to Ca2+(EFmDREAM) in hippocampus and cerebellum of transgenic mice significantly reduced NCX3 mRNA and protein levels without modifying NCX1 and NCX2 expression. Cerebellar granules from EFmDREAM transgenic mice showed increased levels of cytosolic Ca2+and were more vulnerable to increased Ca2+influx after partial opening of voltage-gated plasma membrane Ca2+channels induced by increasing K+in the culture medium but survived better in the conditions of reduced Ca2+influx prevailing in low extracellular K+. Overexpression of NCX3 in EFmDREAM transgenic granules using a lentiviral vector restored the normal survival response to high K+observed in wild-type granules. Thus, the downregulation of the regulator of Ca2+homeostasis NCX3 by Ca2+-regulated DREAM is a striking example of the autoregulatory property of the Ca2+signal in neurons.