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Store-operated Ca2+-entry (SOCE) regulates basal and receptor-triggered Ca2+ signaling with STIM proteins sensing the endoplasmic reticulum (ER) Ca2+ content and triggering Ca2+ entry by gating Orai channels. Although crucial for immune cells, STIM1's role in neuronal Ca2+ homeostasis is controversial. Here, we characterize a splice variant, STIM1B, which shows exclusive neuronal expression and protein content surpassing conventional STIM1 in cerebellum and of significant abundance in other brain regions. STIM1B expression results in a truncated protein with slower kinetics of ER-plasma membrane (PM) cluster formation and I CRAC , as well as reduced inactivation. In primary wild-type neurons, STIM1B is targeted by its spliced-in domain B to presynaptic sites where it converts classic synaptic depression into Ca2+- and Orai-dependent short-term synaptic enhancement (STE) at high-frequency stimulation (HFS). In conjunction with altered STIM1 splicing in human Alzheimer disease, our findings highlight STIM1 splicing as an important regulator of neuronal calcium homeostasis and of synaptic plasticity. [Display omitted] • STIM1B but not STIM1 localizes to presynaptic ER • STIM1B causes increased vesicle release at high demand • STIM1B alters slow Ca2+-dependent inactivation of I CRAC • Splicing alters frequency dependence of synapses and is decreased in AD The role of presynaptic ER in synapse specification is not well known. Ramesh et al. identify an alternative Stim1 splice variant selectively targeted to presynaptic ER where it converts short-term depression into short-term enhancement (STE) in high-demand situations by increasing recruitment of synaptic vesicles. [ABSTRACT FROM AUTHOR]