Neuronal activity regulates astrocytic Nrf2 signaling

Nuclear factor erythroid 2-related factor 2 (Nrf2), the transcriptional master regulator of the stress-induced antioxidant response, plays a key role in neuronal resistance to oxidative stress and glutamate-induced excitotoxicity. Nrf2-mediated neuroprotection is primarily conferred by astrocytes both in vitro and in vivo, but little is known about physiologic signals that regulate neuronal and astrocytic Nrf2 signaling. Here, we report that activity of the Nrf2 pathway in the brain is fine-tuned through a regulatory loop between neurons and astrocytes: elevated neuronal activity leads to secretion of glutamate and other soluble factors, which activate the astrocytic Nrf2 pathway through a signaling cascade that involves group I metabotropic glutamate receptors and intracellular Ca2+. Therefore, regulation of endogenous antioxidant signaling is one of the functions of the neuron-astrocyte tripartite synapse; by matching the astrocyte neuroprotective capacity to the degree of activity in adjacent neuronal synapses, this regulatory mechanism may limit the physiologic costs associated with Nrf2 activation.