Inhibitory and excitatory neuromodulation by hydrogen peroxide: translating energetics to information

Historically, brain neurochemicals have been broadly classified as energetic or informational. However, increasing evidence implicates metabolic substrates and byproducts as signalling agents, which blurs the boundary between energy and information, and suggests the introduction of a new category for translational' substances that convey changes in energy state to information. One intriguing example is hydrogen peroxide (H2O2), which is a small, readily diffusible molecule. Produced during mitochondrial respiration, this reactive oxygen species, can mediate dynamic regulation of neuronal activity and transmitter release by activating inhibitory ATP-sensitive K+ (K-ATP) channels, as well as a class of excitatory non-selective cation channels, TRPM2. Studies using ex vivo guinea pig brain slices have revealed that activity-generated H2O2 can act via K-ATP channels to inhibit dopamine release in dorsal striatum and dopamine neuron activity in the substantia nigra pars compacta. In sharp contrast, endogenously generated H2O2 enhances the excitability of GABAergic projection neurons in the dorsal striatum and substantia nigra pars reticulata by activating TRPM2 channels. These studies suggest that the balance of excitation vs. inhibition produced in a given cell by metabolically generated H2O2 will be dictated by the relative abundance of H2O2-sensitive ion channel targets that receive this translational signal.