Sistently, Stim1 was lately found to activate TRPC3 and mediate mGluR1-dependent slow excitatory postsynaptic potentials in mouse Purkinje neurons (Hartmann et al., 2014). Earlier work showed that SOCE contributes to elevate dendritic Ca2+ concentration in the course of tetanic stimulation and participates to LTP generation at Schaffer collateral-CA1 synapses in hippocampal slices (Baba et al., 2003). Unfortunately, there are no studies in Stim- or Orai-deficient neurons to support this contention at molecular level. As aforementioned, Stim1 ablation prevents the Ca2+ response to synaptic stimulation in cerebellar Purkinje neurons, but that is because of earlier depletion with the ER Ca2+ pool (Hartmann et al., 2014). If SOCE is basally activated to preserve ER Ca2+ concentration, it really is quite likely that the genetic disruption of its constituents will constantly depress Ca2+ transients independently on the function played by SOCE through the synaptic response. We predict that short-term incubations with certain Orai inhibitors could unveil irrespective of whether and how SOCE modulates Ca2+ dynamics in firing neurons (for a list of selective blockers, see Parekh, 2010; Moccia et al., 2014a). SOCE could be relevant to dictate the polarity, i.e., LTD vs. LTP, in the changes in synaptic plasticity. As an example, low (bursts 250 ms) and high Bromfenac COX frequency (bursts 250 ms) mossy fiber discharge induce, respectively, LTD and LTP by activating two distinct patterns of post-synaptic Ca2+ signals in cerebellar granule cells. A low boost in [Ca2+ ]i generated by VOCCs and NMDA receptors elicits LTD, even though a sustained elevation in [Ca2+ ]i related to mGluR1 stimulation final results in LTP (Gall et al., 2005). One may hypothesize that SOCE is selectively engaged in the course of higher, but not low, frequency transmission, resulting from the larger depletion of the ER Ca2+ pool. As a consequence, SOCE would participate towards the enhance in post-synaptic [Ca2+ ]i that triggers the phosphorylation cascade culminating in LTP induction (Higley and Sabatini, 2012). This Cilastatin (sodium) Bacterial hypothesis is consistent using the physicalSOCE Controls Gene Expression in Brain NeuronsBasal SOCE will not only modulate spinogenesis and ER Ca2+ levels; in addition, it drives gene transcription in mouse cerebellar granule cells (Lalonde et al., 2014). Sp4 is often a neuron transcription aspect that governs the expression of numerous tissue-specific and housekeeping genes and is implicated in memory formation and behavioral processes relevant to psychiatric disorders (Zhou et al., 2005; Pinacho et al., 2011). Stim1 is activated in hyperpolarized (i.e., quiescent) granule cells by the partial depletion from the ER Ca2+ pool and relocates into sub-membranal puncta which are juxtaposed to both Orai1 and Orai2. The resulting SOCE triggers Sp4 ubiquitylation and proteasomal degradation, but does not stimulate cAMP response element-binding protein (CREB) phosphorylation. Furthermore, membrane depolarization (i.e., synaptic activity) refills ER Ca2+ load, thereby dismantling Stim1 puncta, deactivating SOCE and, in the end, restoring Sp4 abundance (Lalonde et al., 2014). This study did not examine which Orai isoform mediates SOCE, but Orai2 is the most likely candidate (Hartmann et al., 2014). Furthermore, future investigations will have to assess if this mechanism is deranged in schizophrenia, in which Sp4 down-regulation is associated to illness symptoms (Pinacho et al., 2011; Hooper et al., 2014). We should, on the other hand, point out that Stim1-dependent regulation of Sp4 rep.