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

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.