From Signal to Memory: A Proposed Adaptive Hierarchy Linking Autism-Associated Genes to Sensory Homeostasis

Every nervous system must preserve sensitivity to change while reducing responses to constancy. This review defines that adaptive objective as sensory homeostasis: the process through which 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-associated genes spanning neuronal excitability, synaptic function, intracellular signaling, transcription, and chromatin regulation. This hypothesis-driven narrative review asks whether the established functions of independently identified ASD-associated genes support a directional framework through which genetic vulnerability 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, the review organizes a bounded subset 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 adaptive cellular memory. The resulting 44-gene core contains 32 of the 185 members distributed across all three levels and identifies IP3R-mediated endoplasmic-reticulum Ca2+ release as an important, but not exclusive, Level 1 convergence mechanism in signal generation. The proposed framework predicts distinct proximal defects that converge on abnormal response trajectories across repeated stimulation, providing a testable connection among ASD genetics, adaptive cellular memory, and sensory phenotype.