Spatial Compartmentalization of the Neuronal Endoplasmic Reticulum: Structural Basis of Calcium Signaling and Cellular Homeostasis

The neuronal endoplasmic reticulum (ER) forms a continuous membrane network that extends throughout the soma, dendrites, axons, and synaptic compartments. Although traditionally viewed as a structurally continuous intracellular organelle, recent advances in volume electron microscopy, super-resolution imaging, and live-cell functional analyses have revealed that the ER is highly compartmentalized into specialized structural and molecular domains. These domains organize local Ca 2+ release, store refilling, luminal Ca 2+ redistribution, and inter-organelle communication through membrane contact sites, thereby enabling the diverse physiological functions of the ER. Emerging evidence further indicates that ER topology is a fundamental determinant of diverse ER functions and that disruption of ER architecture is increasingly implicated in the pathogenesis of neurological disorders. In this review, I first summarize the ultrastructural organization of the neuronal ER based on representative electron microscopy observations and then discuss how spatial compartmentalization provides an organizational principle linking ER structure to intracellular signaling, neuronal homeostasis, and neurological disorders.