Persistent adaptation through dual-timescale regulation of ion channel properties

ABSTRACT 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. SIGNIFICANCE STATEMENT Some neurons display a remarkable property: after adapting to environmental challenges, they return to baseline activity that looks unchanged, even though underlying modifications were made. These modifications may persist, shaping how the neuron responds to future perturbations. We term this phenomenon persistent adaptation . Although the underlying mechanisms of persistent adaptations may be diverse, here we demonstrate one possible route: homeostatic regulation of intrinsic excitability. Slow changes in channel density can store a trace of past perturbations, while rapid shifts in channel voltage-dependence can enable immediate recovery during re-exposure.