Abstract: Since the first electron micrograph of “lace-like structures” over 75 years ago, the endoplasmic reticulum (ER) is now viewed as a highly dynamic, constantly remodeling, continuous network of tubules and cisternae that plays an important role in a broad range of cellular activities from calcium regulation to protein synthesis and trafficking. In neurons, the ER extends from the soma through the axon to presynaptic terminals, and throughout the dendritic arbor into as many as half of all postsynaptic dendritic spines at any given time (Falahati et al., 2022). Dendritic spines are small protrusions decorating the branches of the dendritic arbor which receive most of the excitatory synaptic inputs in the central nervous system. Spines compartmentalize the postsynaptic mechanical and chemical responses tailored to the specific input that they receive. In addition to the wide range of shapes and sizes, spines also vary in their molecular and organellar composition, including ER. Recent findings reveal that neurons effectively exploit spine heterogeneity, particularly ER content to differentially tune spine function and structure during synaptic plasticity (Dittmer et al., 2024).