Connecting the Dots: A Computational Framework linking Molecular Regulation, Synaptic Plasticity, and Brain Disorders
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The complexity of brain function emerges from multiscale interactions spanning molecular, synaptic, and circuit levels. While substantial progress has been made in each domain, a unified framework linking molecular perturbations to large-scale brain dysfunctions remains elusive. Here, we introduce a computational framework that bridges molecular regulation and neuronal plasticity, providing mechanistic insights into disease pathogenesis. By creating a Boolean network model of molecular regulatory pathways, we identify two stable states— synaptic potentiation and depression—governed by AMPA receptor trafficking and consistent with Hebbian learning principles. Through in silico knockout simulations mimicking genetic anomalies, our model demonstrates how molecular perturbations cascade across scales, disrupting synaptic plasticity and ultimately driving diverse neurological dysfunctions. The model’s predictions align with a broad range of experimental and clinical data. Our framework establishes a mechanistic foundation for understanding the hierarchical causality of brain disorders, offering a powerful tool for dissecting disease mechanisms and informing targeted therapies.
