Neuronal homeostasis as feedback control: a framework for localizing regulatory dysfunction in neurodevelopmental disorders

Neurons preserve functional activity despite continual changes in synaptic drive, morphology, and membrane protein turnover. This stability is commonly attributed to homeostatic regulation. There is converging evidence that neurodevelopmental disorders (NDDs) may arise from failure of this regulation. Here, we formulate neuronal homeostasis as a negative-feedback control problem comprising a regulated variable, set point, sensor, controller, and effectors. This formulation converts broad claims of impaired homeostasis into mechanistically distinct hypotheses. Dysfunction may arise from sensor miscalibration, a displaced set point, defective controller transduction, incorrect gain, or saturation or loss of an effector’s adjustability. We use this framework to reinterpret evidence from NDDs in which diverse genetic lesions converge on altered excitability, excitatory-inhibitory balance, and circuit stability. The framework yields two central conclusions. First, homeostatic dysfunction should often be direction-specific rather than uniformly deficient, because upward and downward compensation rely on partially separable molecular and physiological mechanisms. Second, electrophysiological measurements are insufficient to identify the governing regulatory rule as degeneracy permits distinct ion-channel configurations to support similar activity, whereas integral feedback allows the same electrophysiological measurements to arise from different regulatory dynamics. Consequently, localizing dysfunction within the loop requires bidirectional perturbations, longitudinal measurement, and computational models that represent a population of models rather than a unique set of parameters. A control-theoretic framework therefore provides both a mechanistic taxonomy and an experimental strategy for determining how neuronal regulation fails in disease.