The endoplasmic reticulum puts a new spin on synaptic tagging

The heterogeneity of the endoplasmic reticulum (ER) makes it a versatile platform for a broad range of homeostatic processes, ranging from calcium regulation to synthesis and trafficking of proteins and lipids. It is not surprising that neurons use this organelle to fine-tune synaptic properties and thereby provide specificity to synaptic inputs. In this review, we discuss the mechanisms that enable activity-dependent ER recruitment into dendritic spines, with a focus on molecular mechanisms that mediate transport and retention of the ER in spines. The role of calcium signaling in spine ER, synaptopodin 'tagging' of active synapses, and the formation of the spine apparatus (SA) are highlighted. Finally, we discuss the role of liquid-liquid phase separation as a possible driving force in these processes.