From Signal to Memory: An Adaptive Hierarchy Linking Autism Risk Genes to Sensory Homeostasis

Every nervous system must preserve sensitivity to change while reducing responses to constancy. We define this adaptive objective as sensory homeostasis: familiar information recedes while unexpected or biologically important events remain salient. Its disruption is particularly relevant to autism spectrum disorder (ASD), in which sensory abnormalities occur across multiple modalities. Large-scale sequencing studies have identified hundreds of ASD-risk genes spanning neuronal excitability, synaptic function, intracellular signaling, transcription, and chromatin regulation. Here, we ask whether the established functions of independently identified ASD-associated genes reconstruct a directional pathway through which genetic vulnerability to ASD could compromise sensory homeostasis. Beginning with a prespecified Autism Sequencing Consortium–derived set of 185 ASD-associated genes, and separately classifying complementary genetic and mechanistic evidence, we organize a bounded subset of genes into three functional levels: generation and spatial organization of intracellular Ca²⁺ signals; interpretation of those signals by electrical, biochemical, synaptic, and transcriptional decoders; and stabilization of selected responses through transcriptional and chromatin-regulatory mechanisms that establish cellular memory.