Abstract
In neurons, stromal interaction molecule (STIM) proteins regulate store-operated Ca2+ entry (SOCE) and are involved in calcium signaling pathways. However, STIM activity in neurological diseases is unclear and should be clarified by studies that are performed in vivo rather than in cultured cells in vitro. The present study investigated the role of neuronal Stim2b protein in zebrafish. We generated stim2b knockout zebrafish, which were fertile and had a regular lifespan. Using various behavioral tests, we found that stim2b−/− zebrafish larvae were hyperactive compared with wild-type fish. The mutants exhibited increases in mobility and thigmotaxis and disruptions of phototaxis. They were also more sensitive to pentylenetetrazol and glutamate treatments. Using lightsheet microscopy, a higher average oscillation frequency and higher average amplitude of neuronal Ca2+ oscillations were observed in stim2b−/− larvae. RNA sequencing detected upregulation of the annexin 3a and gpr39 genes and downregulation of the rrm2, neuroguidin, and homer2 genes. The latter gene encodes a protein that is involved in several processes that are involved in Ca2+ homeostasis in neurons, including metabotropic glutamate receptors. We propose that Stim2b deficiency in neurons dysregulates SOCE and triggers changes in gene expression, thereby causing abnormal behavior, such as hyperactivity and susceptibility to seizures.
Highlights
Stromal interaction molecule (STIM) is a calcium (Ca2+ )-sensing protein that is localized in the endoplasmic reticulum (ER) membrane [1]
The mean amplitude of seizure-like episodes, defined as the distance traveled, was higher in WT fish (Figure 6C). These results showed that stim2b−/− larvae exhibited greater susceptibility to seizures with a low dose of PTZ, but they exhibited a weaker response to the high dose of PTZ
We observed the differential expression of several genes in stim2b−/− larvae
Summary
Stromal interaction molecule (STIM) is a calcium (Ca2+ )-sensing protein that is localized in the endoplasmic reticulum (ER) membrane [1]. STIM2 appears to be crucial in regulating Ca2+ homeostasis in neurons Reductions of both SOCE and basal Ca2+ levels were observed in cortical neurons that were isolated from Stim2−/−. Zebrafish are often used for drug screening, and several neuroactive compounds have been tested in this animal [28,34] Among these compounds are pro-convulsant drugs, such as pentylenetetrazol (PTZ), that induce robust changes in larval behavior and neuronal activity [35]. We took advantage of genome duplication that occurs in zebrafish Through this process, zebrafish possess two genes that encode Stim proteins: stim2a and stim2b [3,4]. The behavioral analyses were supplemented with analyses of neuronal Ca2+ signaling in live zebrafish
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