Oxidative stress in synapse development and function.

Abstract

Oxidative stress, caused by increased levels of reactive oxidative species (ROS), is considered a major contributor to the aging process. How oxidative stress may bring about changes to structures and function in the aging brain is poorly understood. Oxidative stress activates a number of cellular responses, including activation of the Jun-N-terminal kinase (JNK) pathway and autophagy. In addition to their pathological role, ROS also act as signaling molecules. ROS such as nitric oxide have a well-known role in learning and memory. In addition, activation of JNK and its transcriptional effector AP-1 are well-known mediators of synaptic function and growth. Both are essential mediators of physiological correlates of learning and memory such as long-term potentiation. JNK and AP-1 are potently activated and regulated by oxidative stress and mediate protective cellular responses such as autophagy. Recent work at the Drosophila neuromuscular junction implicates autophagy as a regulator of synaptic growth via activation of the JNK signaling pathway. We here outline a framework predicating oxidative stress as a major regulator of synaptic function and growth by the activation of JNK/AP-1 and autophagy. Such responses, we suggest, may underpin some forms of synaptic growth responses and synaptic aging.