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CircuitATLAS is a provenance-grounded systems neuroscience knowledge graph and agentic framework designed to discover novel therapeutic targets for circuitopathies by reasoning over disease phenotypes, circuit substrates, and molecular effectors, while deliberately avoiding direct disease-gene associations. The framework integrates literature-derived relationships, structured datasets, and LLM-extracted information to enable agentic reasoning from phenotypes to feasible molecular interventions. An agent within this system successfully identified ATP1A3 as a control point for cortical excitability, which was subsequently validated experimentally, demonstrating the framework's efficacy in discovering and validating therapeutic targets.
A novel agentic framework and knowledge graph, CircuitATLAS, bypasses direct disease-gene links to uncover non-obvious molecular control points for neurological circuitopathies, successfully identifying and validating ATP1A3 as a target for cortical excitability.
Drug discovery for neurological disease has traditionally centered on the molecules altered by disease. But the molecules that cause pathology are not necessarily the best points from which to reverse it. Here, we ask which otherwise unaltered molecular control points can be engaged to restore pathological neural circuits toward functional states. We present CircuitATLAS, a provenance-grounded systems-neuroscience knowledge graph and agentic framework for target discovery in circuitopathies. It structures literature-derived relationships across diseases, phenotypes, electrophysiology, circuits, brain regions, cell types and molecular effectors, while deliberately excluding direct disease-gene and disease-protein edges to reduce shortcut reasoning. The graph contains 3.83 million nodes and 7.66 million edges, including 5.31 million LLM-extracted relations, and incorporates structured datasets such as the Human Cell Atlas and new multimodal in vivo measurements. We then introduce an agentic workflow that reasons from measurable disease phenotypes through their circuit and cellular substrates to molecular interventions, therapeutic feasibility and clinical constraints. Finally, we introduce a human-governed in vivo lab-in-the-loop linking hypothesis generation to experimental iteration. Within this framework an agent nominated ATP1A3, the neuronal alpha3 Na+/K+-ATPase, as a control point on cortical excitability; interneuron-restricted expression of ATP1A3 abolished the beta- and gamma-band response to a focal 4-aminopyridine challenge in vivo, and the validated target was then carried into a structure-guided small-molecule campaign terminating in a defined assay to resolve the direction of modulation. CircuitATLAS thus provides a framework for discovering therapeutics based not only on what is molecularly disrupted in disease, but on what can be controlled to restore circuit function.