Protein oxidation inhibits NO-mediated signaling pathway for synaptic plasticity.

Oxidative stress is a primary factor inducing brain dysfunction in aged animals. However, how oxidation affects brain function is not fully understood. Here we show that oxidation inhibits signaling pathways essential for synaptic plasticities in the cerebellum. We first revealed that nitric oxide (NO)-dependent plasticities at the parallel fiber-Purkinje cell synapse (PF synapse) were impaired in the cerebellar slices from aged mice, suggesting a possible inhibitory action of protein oxidation by endogenous reactive oxygen species. PF-synaptic plasticities were also blocked in the cerebellar slices from young mice preincubated with oxidizing agents or thiol blocker. Because the treatment of the slices with the oxidizing agent did not affect basic electrophysiological properties of excitatory postsynaptic current of PF (PF-EPSC) and did not occlude the synaptic plasticities, oxidation was revealed to specifically inhibit signaling pathways essential for PF-synaptic plasticities. Finally, biochemical analysis confirmed the idea that inhibitory action of protein oxidation on the PF-synaptic plasticities was mediated by impairment of nitric oxide-induced protein S-nitrosylation. Therefore, oxidation was revealed to inhibit the S-nitrosylation-dependent signaling pathway essential for synaptic plasticity in a "competitive" manner.