Oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases and stroke. However, low levels of reactive oxygen species (ROS) function as second messengers in many neuronal signal transduction pathways, which could thus be affected either by the disease process itself or by activation of endogenous antioxidant responses. The long term goal of this research is to define how endogenous antioxidant signaling regulates synaptic transmission and thus shapes vulnerability of synaptic networks to oxidative stress. The specific objective of this application is to elucidate molecular mechanisms underlying synaptic function of Nrf2, the transcriptional regulator of inducible antioxidant response that is a key determinant of neuronal susceptibility to injury. Our central hypothesis is that astrocytes respond to neuronal activity by enhancing current flow through ROS-sensitive glutamatergic NMDA receptors (NMDARs, the key mediators of both synaptic plasticity and glutamate excitotoxicity), while simultaneously activating Nrf2 pathway to protect neurons from ROS-induced damage and neurotoxicity. This hypothesis was formulated on the basis of the strong preliminary data obtained in our laboratory and will be tested by pursuing four specific aims. First, we will elucidate the molecular mechanism that underlies activity-mediated induction of Nrf2 pathway in neuron-astrocyte co-cultures. Second, we will establish whether neuroprotection induced by synaptic activity is enhanced when neurons are co-cultured with astrocytes. Third, we will determine how glial cells increase neuronal NMDAR current density in the mixed neuron-glia environment. Fourth, we will dissect the neuron-glia signal transduction cascade that underlies Nrf2-mediated regulation of NMDAR signaling and determine the effect of Nrf2 pathway activation on circuit plasticity.
These aims will be accomplished through a combination of molecular, biochemical, electrophysiological, cell biological, and toxicological approaches whose feasibility in our hands has been established through the preliminary data;to dissect the roles of individual cell types, we will use primary neuronal, glial, and mixed hippocampal cultures, as well as neuron-glia co-cultures of defined cellular composition. The overall approach takes the field in a new direction by focusing on the role of neuron- glia interactions in the regulation and function of Nrf2 signaling in the brain, an aspect of Nrf2 biology that has not yet been investigated. Completion of the proposed research is expected to advance our understanding of ROS signaling and Nrf2 physiology in the brain;ultimately, such knowledge will enable development of pharmacologic treatments capable of harnessing neuroprotective power of endogenous antioxidants without negatively affecting neuronal activity and synaptic signaling.

Public Health Relevance

By advancing our understanding of Nrf2 pathway biology in the brain, the proposed research will uncover optimal molecular and cellular targets for prevention and/or treatment of Alzheimer disease and other neurologic disorders with impaired synaptic plasticity. Thus, it is aligned with the NIH mission to foster fundamental scientific discoveries and innovative research strategies that form a basis for protection and improvement of public health.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073765-02
Application #
8337833
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Corriveau, Roderick A
Project Start
2011-09-30
Project End
2016-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$337,969
Indirect Cost
$119,219
Name
University of California San Francisco
Department
Pathology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Habas, Agata; Hahn, Junghyun; Wang, Xianhong et al. (2014) Reply to Deighton et al.: Neuronal activity regulates distinct antioxidant pathways in neurons and astrocytes. Proc Natl Acad Sci U S A 111:E1821-2
Potts, Matthew B; Siu, Jason J; Price, James D et al. (2014) Analysis of Mll1 deficiency identifies neurogenic transcriptional modules and Brn4 as a factor for direct astrocyte-to-neuron reprogramming. Neurosurgery 75:472-82; discussion 482
Habas, Agata; Hahn, Junghyun; Wang, Xianhong et al. (2013) Neuronal activity regulates astrocytic Nrf2 signaling. Proc Natl Acad Sci U S A 110:18291-6