Control of Ca²⁺ flux between the cytosol and intracellular Ca²⁺ 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 Ca²⁺ into the ER. Here, we describe a novel, additional role for STIM1, the regulation of free cytosolic Ca²⁺, 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 Ca²⁺ homeostasis of particular importance. By using Purkinje neuron-specific STIM1 knock-out (STIM1^PKO) male mice, we found that the deletion of STIM1 delayed clearance of cytosolic Ca²⁺ 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^PKO 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.SIGNIFICANCE STATEMENT Stromal interaction molecule 1 (STIM1), which regulates the refilling of ER Ca²⁺, has been investigated in several systems including the CNS. In addition to a previous study showing that STIM1 regulates dendritic ER Ca²⁺ 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 Ca²⁺ clearance of the soma during spike firing, and the interruption of this cytosolic Ca²⁺ clearing disrupts neuronal excitability and cerebellar memory consolidation. Our results provide new insights into neuronal functions of STIM1 from single neuronal Ca²⁺ dynamics to behavior level.

Dayoon Jung

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