Reactive oxygen species mediate activity-dependent neuron-glia signaling in output fibers of the hippocampus

Nonsynaptic signaling is becoming increasingly appreciated in studies of ac tivity-dependent changes in the nervous system. We investigated the types o f neuronal activity that elicit nonsynaptic communication between neurons a nd glial cells in hippocampal output fibers. High-frequency, but not low-fr equency, action potential firing in myelinated CA1 axons of the hippocampus resulted in increased phosphorylation of the oligodendrocyte-specific prot ein myelin basic protein (MBP). This change was blocked by tetrodotoxin, in dicating that axonally generated action potentials were necessary to regula te the phosphorylation state of MBP. Furthermore, scavengers of the reactiv e oxygen species superoxide and hydrogen peroxide and nitric oxide synthase inhibitors prevented activation of this neuron-glia signaling pathway. The se results indicate that, during periods of increased neuronal activity in area CA1 of the hippocampus, reactive oxygen and nitrogen species are gener ated, which diffuse to neighboring oligodendrocytes and result in post-tran slational modifications of MBP, a key structural protein in myelin. Thus, i n addition to their well-known capacity for activity-dependent neuron-neuro n signaling, hippocampal pyramidal neurons possess a mechanism for activity -dependent neuron-glia signaling.