Mitochondria constantly release various amounts of superoxide anions which are rapidly converted to H₂O₂ and modulate cellular redox state and redox-sensitive proteins. Such redox signaling is part of both physiological and pathophysiological brain function. We therefore analyzed the H₂O₂-mediated responses of hippocampal neurons. Oxidation of redox sensitive dyes confirmed the membrane permeability of H₂O₂ in cultured neurons and acute slices, thus H₂O₂ may not only act at its generation site, but may affect neighboring cells as well. 1 mM H₂O₂ did not depress basal synaptic function or paired-pulse facilitation, but it postponed the onset of hypoxic depression. Mitochondria depolarized only slightly in response to 1 mM H₂O₂; cellular NADH levels decreased -obviously due to direct oxidation. In cultured neurons 0.2 mM H₂O₂ moderately increased intracellular Ca²⁺. This Ca²⁺ rise was not prevented by 2 mM Ni²⁺, Ca²⁺-free solution, mitochondrial uncoupling by 1 mM FCCP or chelating Fe ²⁺. Pretreatment with 1 mM ryanodine ameliorated the Ca²⁺ rise, while 25 mM ryanodine and 10 mM ruthenium red depressed it. In conclusion, low levels of H₂O₂ release Ca²⁺ from internal stores - obviously the endoplasmic reticulum. This modulation of Ca²⁺ sequestration by redox state and ROS levels could play a pivotal role in adjusting cellular function to oxidative stress.

Supported by: DFG (SFB 406, CMPB) and Göttingen University