Mitochondrial calcium, a potential sensor for homeostatic synaptic plasticity

Neural function is maintained through homeostatic mechanisms that are engaged following perturbations to the nervous system. Homeostatic plasticity is thought to be critical for establishing and stabilizing appropriate levels of network function. Neurons are proposed to detect deviations in activity through intracellular calcium signaling, such that changes in calcium levels initiate compensatory mechanisms that restore activity and calcium to baseline. This sensing process is generally assumed to occur in the cytoplasm, however, recent work suggests that it may reside inside mitochondria. We test this in the chick embryo (either sex) spinal cord. We show that perturbations known to induce homeostatic plasticity preferentially alter the mitochondrial proteome, including components of the tricarboxylic acid (TCA) cycle, a pathway sensitive to calcium entry into mitochondria. We then tested whether calcium influx into the mitochondrial matrix contributes to the induction of homeostatic plasticity in motoneurons. Pharmacological blockade of the mitochondrial calcium uniporter (MCU), which mediates calcium entry into the matrix, produced a robust and sustained increase in spontaneous network activity (SNA). Using Ru265 to inhibit MCU function, we confirmed a reduction in mitochondrial calcium, while cytoplasmic calcium levels were largely unchanged or slightly elevated. MCU blockade was accompanied by an increase in excitatory synaptic strength consistent with homeostatic synaptic plasticity. The underlying mechanisms overlapped with those previously described in this preparation following activity or neurotransmitter blockade. Together, these findings support a model in which mitochondria contribute to the initiation of homeostatic synaptic plasticity, potentially by sensing changes in calcium transients within the mitochondrial matrix.Significance Statement Homeostatic plasticity is thought to play a critical role in maintaining circuit function. Although substantial progress has been made in identifying the mechanisms underlying the expression of homeostatic plasticity, the upstream triggers remain poorly understood. Cytoplasmic calcium has been proposed as a key signal in the detection of perturbations in neural circuit activity and in initiating compensatory responses. Here, we present findings consistent with the idea that the sensor for network activity and homeostatic synaptic plasticity tracks mitochondrial calcium. Identifying the sensor that initiates homeostatic mechanisms will be essential for understanding the functional objectives of this form of plasticity and may provide a foundation for pharmacologically targeting this pathway in conditions characterized by altered network activity.