Local H₂O₂ production in septo-hippocampal circuitry modulates plasticity and behavior without inducing widespread...

The precise regulation of synaptic plasticity by local redox states represents a fundamental, yet poorly understood, dimension of neural circuit control. Traditional models of oxidative stress often invoke global damage, failing to resolve how specific neuronal circuits utilize hydrogen peroxide (H₂O₂) for signaling. Here, we developed a chemogenetic strategy to interrogate this question, targeting the expression of D-amino acid oxidase (DAAO) for the spatially and temporally controlled production of H₂O₂ within distinct neuronal subpopulations of the medial septal area (MSA). Contrary to inducing widespread oxidative damage, this approach revealed that local H₂O₂ flux acts as a potent, bidirectional regulator of circuit function. We discovered that DAAO expression in MSA neurons, even without exogenous substrate, is sufficient to enhance hippocampal long-term potentiation (LTP) and induce transient sensorimotor deficits, unmasking a tonic redox tone set by endogenous D-amino acids. Strikingly, we identified a previously unknown hierarchical organization within the septo-hippocampal circuit: while cholinergic input is permissive for LTP induction, non-cholinergic MSA neurons function as a master gain-control system, whose redox state dictates the ultimate magnitude of synaptic changes. Our findings establish a new paradigm, moving beyond oxidative stress as a purely pathological entity to reveal how compartmentalized ROS generation enables precise, cell-type-specific tuning of higher-order brain functions. This work provides a foundational framework for understanding redox coding in the brain.