Organelle-Specific Sensors for Monitoring Ca²⁺ Dynamics in Neurons

Calcium (Ca²⁺) plays innumerable critical functions in neurons ranging from regulation of neurotransmitter release and synaptic plasticity to activity-dependent transcription. Therefore, more than any other cell types, neurons are critically dependent on spatially and temporally controlled Ca²⁺ dynamics. This is achieved through an exquisite level of compartmentalization of Ca²⁺ storage and release from various organelles. The function of these organelles in the regulation of Ca²⁺ dynamics has been studied for decades using electrophysiological and optical methods combined with pharmacological and genetic alterations. Mitochondria and the endoplasmic reticulum (ER) are among the organelles playing the most critical roles in Ca²⁺ dynamics in neurons. At presynaptic boutons, Ca²⁺ triggers neurotransmitter release and synaptic plasticity, and postsynaptically, Ca²⁺ mobilization mediates long-term synaptic plasticity. To explore Ca²⁺ dynamics in live cells and intact animals, various synthetic and genetically encoded fluorescent Ca²⁺ sensors were developed, and recently, many groups actively increased the sensitivity and diversity of genetically encoded Ca²⁺ indicators (GECIs). Following conjugation with various signal peptides, these improved GECIs can be targeted to specific subcellular compartments, allowing monitoring of organelle-specific Ca²⁺ dynamics. Here, we review recent findings unraveling novel roles for mitochondria- and ER-dependent Ca²⁺ dynamics in neurons and at synapses.