INTRODUCTION: Calcium signaling plays a crucial role in the regulation of neuronal function and survival. STIM2 is a key component of store-operated calcium entry (SOCE), which maintains intracellular calcium homeostasis. Our recent data demonstrate that knockout of stim2 in zebrafish induces a glaucomatous-like retinal neurodegenerative phenotype. Intracellular calcium fluctuations are known to regulate microglial migration, functional polarization, phagocytosis, and cytokine release. Increased intracellular calcium levels are associated with microglial activation, a process implicated in neurodegeneration.

AIM(S): To elucidate the mechanisms by which loss of stim2 contributes to neuronal degeneration in the zebrafish retina.

METHOD(S): Immunohistochemistry, transmission electron microscopy.

RESULTS: In stim2 KO retinas, we observed a ~1.8-fold reduction in the number of GABAergic neurons in the inner nuclear layer and a ~1.3-fold reduction in photoreceptor cell density. Moreover, transmission electron microscopy revealed narrowing of the inner plexiform layer (IPL) and ganglion cell layer (GCL), accompanied by a significant decrease in dendritic density and ganglion cell number. Additionally, in photoreceptors, mitochondrial cristae area was reduced by ~50%, indicating severe impairment of mitochondrial structure and energy metabolism.

CONCLUSIONS: We propose that impaired STIM2-dependent calcium signaling alters microglial behavior, promoting neuroinflammation and contributing to neuronal loss. This model potentially offers a new approach to studying the role of calcium dysregulation and microglia in glaucomatous-like retinal degeneration and may reveal novel therapeutic targets for neurodegenerative diseases.

FINANCIAL SUPPORT: Preludium Grant NCN 2023/49/N/NZ3/02921