In vivo hydrogen peroxide diffusivity in brain tissue supports volume signaling activity

Abstract

Hydrogen peroxide is a major redox signaling molecule underlying a novel paradigm of cell function and communication. A role for H2O2 as an intercellular signaling molecule and neuromodulator in the brain has become increasingly apparent, with evidence showing this biological oxidant to regulate neuronal polarity, connectivity, synaptic transmission and tuning of neuronal networks. This notion is supported by its ability to diffuse in the extracellular space, from source of production to target. It is, thus, crucial to understand extracellular H2O2 concentration dynamics in the living brain and the factors which shape its diffusion pattern and half-life. To address this issue, we have used a novel microsensor to measure H2O2 concentration dynamics in the brain extracellular matrix both in an ex vivo model using rodent brain slices and in vivo. We found that exogenously applied H2O2 is removed from the extracellular space with an average half-life of t1/2 = 2.2 s in vivo. We determined the in vivo effective diffusion coefficient of H2O2 to be D* = 2.5 × 10-5 cm2 s-1. This allows it to diffuse over 100 μm in the extracellular space within its half-life. Considering this, we can tentatively place H2O2 within the class of volume neurotransmitters, connecting all cell types within the complex network of brain tissue, regardless of whether they are physically connected. These quantitative details of H2O2 diffusion and half-life in the brain allow us to interpret the physiology of the redox signal and lay the pavement to then address dysregulation in redox homeostasis associated with disease processes.