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The Journal of Neuroscience, February 1, 2006, 26(5):1604-1615; doi:10.1523/JNEUROSCI.4722-05.2006

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Development/Plasticity/Repair
A Specific Role for NR2A-Containing NMDA Receptors in the Maintenance of Parvalbumin and GAD67 Immunoreactivity in Cultured Interneurons

Jefferson W. Kinney, Christopher N. Davis, Iustin Tabarean, Bruno Conti, Tamas Bartfai, and M. Margarita Behrens

The Harold L. Dorris Neurological Research Center, Molecular and Integrative Neurosciences Department, The Scripps Research Institute, La Jolla, California 92037

Correspondence should be addressed to M. Margarita Behrens, Division of Geriatrics, Department of Medicine, University of California San Diego, Stein Clinical Research Building, Room 126, La Jolla, CA 92093. Email: mbehrens{at}ucsd.edu

Several lines of evidence suggest that a hypoglutamatergic condition may induce a phenotypic loss of cortical parvalbumin (PV)-positive GABAergic interneurons, such as that observed in brain tissue of schizophrenic subjects. However, it is not known whether the loss of PV interneurons is a consequence of the hypoglutamatergic condition or a secondary aspect of the disease. We characterized the signaling and subunit expression of NMDA receptors in cultured cortical PV interneurons and determined whether a hypoglutamatergic condition, created by direct application of sublethal concentrations of ketamine or subunit-selective NMDA receptor antagonists, can affect the expression of the GABAergic markers as observed in vivo. Real-time PCR performed on mRNA isolated from single neurons showed that PV interneurons present a fivefold higher NR2A/NR2B ratio than pyramidal neurons. Brief, nontoxic, exposure to NMDA led to an increase in ERK1/2 (extracellular signal-regulated kinase 1/2) and cAMP response element-binding protein phosphorylation in PV interneurons, and this increase was blocked by the NR2A-selective antagonist NVP-AAM077. Application of the nonselective NMDA receptor antagonist ketamine, at sublethal concentrations, induced a time and dose-dependent decrease in parvalbumin and GAD67 immunoreactivity specifically in PV interneurons. These effects were reversible and were also observed with the NR2A-selective antagonist, whereas the NR2B-selective antagonist Ro-25-6981 only partially reduced GAD67 immunoreactivity. Coexposure to the calcium channel opener BayK, or the group I metabotropic glutamate receptor agonist DHPG [(RS)-3,5-dihydroxyphenylglycine] attenuated the decrease in GAD67 and parvalbumin induced by the NMDA receptor antagonists. These results suggest that the activity of NR2A-containing NMDA receptors play a pivotal role in the maintenance of the GABAergic function of PV interneurons.

Key words: NMDA receptors; parvalbumin; hypoglutamatergic; GABAergic; schizophrenia; mGluR5

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Received July 28, 2005; revised Dec. 19, 2005; accepted Dec. 21, 2005.

Correspondence should be addressed to M. Margarita Behrens, Division of Geriatrics, Department of Medicine, University of California San Diego, Stein Clinical Research Building, Room 126, La Jolla, CA 92093. Email: mbehrens{at}ucsd.edu

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