Persistent Adaptation through Dual-Timescale Regulation of Ion Channel Properties.

Neurons are terminally differentiated cells that adapt to maintain stable function over years, despite encountering a wide range of environmental perturbations. Some adaptations are transient, fading once the perturbation ends. Others are persistent, continuing to influence a neuron's responses to future challenges even after baseline conditions are restored. These persistent adaptations are especially intriguing because some remain undetectable under normal conditions-only becoming apparent upon re-exposure to a perturbation. Among the many mechanisms that may contribute to persistent adaptation, we investigate one based on the regulation of intrinsic currents. Using a computational model of activity-dependent homeostasis, we show that slow changes in channel density can encode the influence of past experience and shape future responses while rapid shifts in ion channel voltage-dependence provide immediate compensation during perturbations. Together, these dual processes tune a neuron's intrinsic excitability, enabling persistent adaptation.