H₂O₂ induces delayed hyperexcitability in nucleus tractus solitarii neurons

Hydrogen peroxide (H₂O₂) is a stable reactive oxygen species and potent neuromodulator of cellular and synaptic activity. Centrally, endogenous H₂O₂ is elevated during bouts of hypoxia-reoxygenation, a variety of disease states, and aging. The nucleus tractus solitarii (nTS) is the central termination site of visceral afferents for homeostatic reflexes and contributes to reflex alterations during these conditions. We determined the extent to which H₂O₂ modulates synaptic and membrane properties in nTS neurons in rat brainstem slices. Stimulation of the tractus solitarii (which contains the sensory afferent fibers) evoked synaptic currents that were not altered by 10-500 μM H₂O₂. However, 500 μM H₂O₂ modulated several intrinsic membrane properties of nTS neurons, including a decrease in input resistance (R(i)), hyperpolarization of resting membrane potential (RMP) and action potential (AP) threshold (THR), and an initial reduction in AP discharge to depolarizing current. H₂O₂ increased conductance of barium-sensitive potassium currents, and block of these currents ablated H₂O₂-induced changes in RMP, Ri and AP discharge. Following washout of H₂O₂ AP discharge was enhanced due to depolarization of RMP and a partially maintained hyperpolarization of THR. Hyperexcitability persisted with repeated H₂O₂ exposure. H₂O₂ effects on RMP and THR were ablated by intracellular administration of the antioxidant catalase, which was immunohistochemically identified in neurons throughout the nTS. Thus, H₂O₂ initially reduces excitability of nTS neurons that is followed by sustained hyperexcitability, which may play a profound role in cardiorespiratory reflexes.