Functional implications of compartment-specific homeostatic regulation and the feasibility of independent local feedback signals

Neurons regulate their average firing rate by adjusting their synaptic strength and intrinsic excitability. Both forms of homeostatic regulation utilize changes in intracellular calcium as a feedback signal to adjust ion channel densities. But two properties cannot be independently regulated using a single feedback signal, suggesting that either synaptic scaling and excitability regulation are linked by a shared feedback signal or that local calcium changes encode separate feedback signals. Past studies on homeostatic regulation have focused on global calcium changes but spatially restricted calcium changes also occur. We hypothesized that local perturbation-induced calcium changes encode separate feedback signals. Simulations in a simple two-compartment model confirmed that a perturbation applied to one or the other compartment induces local compensation only if the feedback is compartment-specific. Simulations in a biophysically detailed multicompartment model with realistic calcium handling confirmed that dendritic and somatic calcium signals remain relatively segregated and can, therefore, mediate homoeostatic regulation independently in subcellular compartments. Strong perturbations (as often tested experimentally) triggered widespread compensation because local compensation was overwhelmed. Non-local compensation also occurred when the spatial segregation of calcium signaling was weakened. Our results demonstrate the plausibility of spatially segregated calcium changes encoding separate feedback signals so that homeostatic changes can be locally controlled. Our results also highlight that whereas local homeostatic regulation nullifies local perturbations through compensation within the affected compartment, non-local regulation causes widespread compensatory changes that, while restoring the neurons overall input-output relationship, distorts the input-output relationship of individual compartments, with potentially important consequences.