Control of Ca flux between the cytosol and intracellular Ca stores is essential for maintaining normal cellular function. It has been well established in both neuronal and non-neuronal cells that stromal interaction molecule 1 (STIM1) initiates and regulates refilling Ca into the ER. Here, we describe a novel, additional role for STIM1, the regulation of free cytosolic Ca, and the consequent control of spike firing in neurons. Among central neurons, cerebellar Purkinje neurons express the highest level of STIM1, and they fire continuously in the absence of stimulation, making somatic Ca homeostasis of particular importance. By using Purkinje neuron-specific STIM1 knock-out (STIM1) male mice, we found that the deletion of STIM1 delayed clearance of cytosolic Ca in the soma during ongoing neuronal firing. Deletion of STIM1 also reduced the Purkinje neuronal excitability and impaired intrinsic plasticity without affecting long-term synaptic plasticity. In vestibulo-ocular reflex learning, STIM1 male mice showed severe deficits in memory consolidation, whereas they were normal in memory acquisition. Our results suggest that STIM1 is critically involved in the regulation of the neuronal excitability and the intrinsic plasticity of the Purkinje neurons as well as cerebellar memory consolidation. Stromal interaction molecule 1 (STIM1), which regulates the refilling of ER Ca, has been investigated in several systems including the CNS. In addition to a previous study showing that STIM1 regulates dendritic ER Ca refilling and mGluR1-mediated synaptic transmission, we provide compelling evidence describing a novel role of STIM1 in spike firing Purkinje neurons. We found that STIM1 regulates cytosolic Ca clearance of the soma during spike firing, and the interruption of this cytosolic Ca clearing disrupts neuronal excitability and cerebellar memory consolidation. Our results provide new insights into neuronal functions of STIM1 from single neuronal Ca dynamics to behavior level.

Long-term depression (LTD) at the parallel fiber (PF)-to-cerebellar Purkinje cell (PC) synapse is implicated in the output of PCs, the sole output of the cerebellar cortex. In addition to synaptic plasticity, intrinsic excitability is also one of the components that determines PC output. Although long-term potentiation of intrinsic excitability (LTP-IE) has been suggested, it has yet to be investigated how PF-PC LTD modifies intrinsic excitability of PCs. Here, we show that pairing of the PF and climbing fiber (CF) for PF-PC LTD induction evokes LTD-IE in cerebellar PCs from male C57BL/6 mice. Interestingly, this intrinsic plasticity showed different kinetics from synaptic plasticity, but both forms of plasticity share Ca 2ϩ signaling and protein kinase C pathway as their underlying mechanism. Although smallconductance Ca 2ϩ -activated K ϩ channels play important roles in LTP-IE, no direct implication has been found. After PF-PC LTD induction, neither the temporal summation of dendritic EPSP nor the power of spike frequency adaptation is changed, indicating that cerebellar LTD executes the information processing in a quantitative way without quality changes of synaptic integration and generation of output signals. Our results suggest that LTD-IE may have a synergistic effect with synaptic depression on the total net output of neurons by amplifying the modification of PF synaptic transmission.

Mutations in RAS signaling pathway components cause diverse neurodevelopmental disorders, collectively called RASopathies. Previous studies have suggested that dysregulation in RAS–extracellular signal–regulated kinase (ERK) activation is restricted to distinct cell types in different RASopathies. Some cases of Noonan syndrome (NS) are associated with gain-of-function mutations in the phosphatase SHP2 (encoded by PTPN11); however, SHP2 is abundant in multiple cell types, so it is unclear which cell type(s) contribute to NS phenotypes. Here, we found that expressing the NS-associated mutant SHP2D61G in excitatory, but not inhibitory, hippocampal neurons increased ERK signaling and impaired both long-term potentiation (LTP) and spatial memory in mice, although endogenous SHP2 was expressed in both neuronal types. Transcriptomic analyses revealed that the genes encoding SHP2-interacting proteins that are critical for ERK activation, such as GAB1 and GRB2, were enriched in excitatory neurons. Accordingly, expressing a dominant-negative mutant of GAB1, which reduced its interaction with SHP2D61G, selectively in excitatory neurons, reversed SHP2D61G-mediated deficits. Moreover, ectopic expression of GAB1 and GRB2 together with SHP2D61G in inhibitory neurons resulted in ERK activation. These results demonstrate that RAS-ERK signaling networks are notably different between excitatory and inhibitory neurons, accounting for the cell type–specific pathophysiology of NS and perhaps other RASopathies.

Accurate lateralization is important to improve treatment outcomes in horizontal semicircular canal (HSCC) benign paroxysmal positional vertigo (BPPV). To determine the involved side in HSCC-BPPV, the intensity of nystagmus has been compared in a head-roll test (HRT) and the direction of nystagmus was evaluated in a bow and lean test (BLT). The aim of this study is to compare the results of a BLT with those of a HRT for lateralization of HSCC-canalolithiasis and cupulopathy (heavy cupula and light cupula), and evaluate treatment outcomes in patients with HSCC-canalolithiasis. We conducted retrospective case reviews in 66 patients with HSCC-canalolithiasis and 63 patients with HSCC-cupulopathy. The affected side was identified as the direction of bowing nystagmus on BLT in 55 % (36 of 66) of patients with canalolithiasis, which was concordant with the HRT result in 67 % (24 of 36) of cases (concordant group). Lateralization was determined by comparison of nystagmus intensity during HRT in 30 patients who did not show bowing or leaning nystagmus. The remission rate after the first treatment was 71 % (17 of 24) in the concordant group and 45 % (5 of 11) in the discordant group. Both bowing and leaning nystagmus were observed in all patients with cupulopathy, and the side of the null plane was identified as the affected side. In conclusion, bowing and/or leaning nystagmus were observed in only 55 % of patients with HSCC-canalolithiasis, and the first treatment based on the result of BLT alone was effective in only 45 % of the patients in whom the BLT and HRT were discordant, which may suggest that the usefulness of BLT in lateralizing the HSCC-canalolithiasis may be limited.