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The Journal of Neuroscience, February 25, 2009, 29(8):2545-2552; doi:10.1523/JNEUROSCI.0133-09.2009

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Development/Plasticity/Repair
NMDA Receptor Activation Increases Free Radical Production through Nitric Oxide and NOX2

Helene Girouard, Gang Wang, Eduardo F. Gallo, Josef Anrather, Ping Zhou, Virginia M. Pickel, and Costantino Iadecola

Division of Neurobiology, Weill Cornell Medical College, New York, New York 10021

Correspondence should be addressed to Dr. Costantino Iadecola, Division of Neurobiology, Weill Cornell Medical College, 407 East 61st Street, RR303, New York, NY 10065. Email: coi2001{at}med.cornell.edu

Reactive oxygen species (ROS) and nitric oxide (NO) participate in NMDA receptor signaling. However, the source(s) of the ROS and their role in the increase in cerebral blood flow (CBF) induced by NMDA receptor activation have not been firmly established. NADPH oxidase generates ROS in neurons, but there is no direct evidence that this enzyme is present in neurons containing NMDA receptors, or that is involved in NMDA receptor-dependent ROS production and CBF increase. We addressed these questions using a combination of in vivo and in vitro approaches. We found that the CBF and ROS increases elicited by topical application of NMDA to the mouse neocortex were both dependent on neuronal NO synthase (nNOS), cGMP, and the cGMP effector kinase protein kinase G (PKG). In mice lacking the NADPH oxidase subunit NOX2, the ROS increase was not observed, but the CBF increase was still present. Electron microscopy of the neocortex revealed NOX2 immunolabeling in postsynaptic somata and dendrites that also expressed the NMDA receptor NR1 subunit and nNOS. In neuronal cultures, the NMDA-induced increase in ROS was mediated by NADPH oxidase through NO, cGMP and PKG. We conclude that NADPH oxidase in postsynaptic neurons generates ROS during NMDA receptor activation. However, NMDA receptor-derived ROS do not contribute to the CBF increase. The findings establish a NOX2-containing NADPH oxidase as a major source of ROS produced by NMDA receptor activation, and identify NO as the critical link between NMDA receptor activity and NOX2-dependent ROS production.

Key words: cerebral blood flow; neurovascular coupling; NADPH oxidase; NO electrode; dihydroethidium; iNOS

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Received Jan. 10, 2009; accepted Jan. 27, 2009.

Correspondence should be addressed to Dr. Costantino Iadecola, Division of Neurobiology, Weill Cornell Medical College, 407 East 61st Street, RR303, New York, NY 10065. Email: coi2001{at}med.cornell.edu

eLetters:

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Is the protection by tat-NR2B9c through partially reducing the ROS generation after stroke?

Rao M Adibhatla

J. Neurosci. Online, 16 Mar 2009 [Full text]

Re: Is the protection by tat-NR2B9c through partially reducing the ROS generation after stroke?

Costantino Iadecola, et al.

J. Neurosci. Online, 20 Mar 2009 [Full text]

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