Brain Research 951 (2002) 166–176 www.elsevier.com / locate / bres Research report Alterations in regional brain metabolism in genetic and pharmacological models of reduced NMDA receptor function * Gary E. Duncan , Seiya Miyamoto, Hongbin Gu, Jeffrey A. Lieberman, Beverly H. Koller, John N. Snouwaert Department of Psychiatry, CB [7090, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7090, USA Accepted 7 May 2002 Abstract A mouse line has been developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor [Cell 98 (1999) 427]. These NR1 hypomorphic mice represent an experimental model of reduced NMDA receptor function that may be relevant to the pathophysiology of schizophrenia. To further characterize the neurobiological phenotype resulting from developmental NMDA receptor 14 hypofunction, regional brain metabolic activity was assessed by autoradiographic analysis of C-2-deoxyglucose (2-DG) uptake. In addition, ligand binding to NMDA, AMPA, and kainate receptors was measured by quantitative autoradiography. MK-801 binding to 3 NMDA receptors was reduced markedly throughout the brain of the NR1 hypomorphic mice. However, no alteration in H-AMPA or 3 H-kainate binding was apparent in any region examined. Neuroanatomically specific alterations in regional 2-DG uptake were observed in the NR1 hypomorphic animals. Reduced relative 2-DG uptake was observed in the medial prefrontal and anterior cingulate cortices. Altered patterns of 2-DG uptake were also found in neocortical regions, with selective reductions of uptake in layer 6 in frontal regions of somatosensory and motor cortices. These data indicate alterations in cortical circuitry in the NR1 hypomorphic animals and are consistent with functional imaging studies in chronic schizophrenia patients which typically show reduced frontal cortical metabolic activity. Reduced relative 2-DG uptake was also found in the caudate, accumbens, hippocampus, and select thalamic regions in the NR1-deficient mice. However, in many other brain regions no alteration in 2-DG uptake was observed. The alterations in 2-DG uptake in the NR1 hypomorphic mice were distinctly different compared to those observed after acute challenge with the selective NMDA antagonist MK-801 in wild-type mice. The altered patterns of brain 2-DG uptake in the NR1 hypomorphic mice found in the present work, together with the altered behavioral phenotypes previously described, suggest that the mice may provide a valuable model to study novel therapeutic strategies to counteract the neurobiological consequences of chronic developmental NMDA receptor hypofunction.  2002 Elsevier Science B.V. All rights reserved. Keywords: NMDA receptor; NR1 hypomorphic mouse 1. Introduction models involving challenge with NMDA antagonists better replicate a broader range of clinical symptoms of schizo- The induction of schizophrenia-like symptoms by sub- phrenia. For example, amphetamine challenge induces anesthetic doses of NMDA antagonists suggests that positive psychotic symptoms and is a good model for reduced NMDA receptor function could contribute to the paranoid schizophrenia [8,31,36]. However, the negative pathophysiology of schizophrenia [13,14,26,34,44]. Com- and cognitive symptoms that are equally prominent in pared to other psychopharmacological models of psycho- schizophrenic patients are not induced by psycho- sis, such as challenge with dopaminergic psychostimulants, stimulants. By contrast, administration of NMDA antago- nists induces positive, negative and cognitive symptoms that are difficult to distinguish from symptoms of schizo- *Corresponding author. Tel.: 11-919-966-8237; fax: 11-919-966- phrenia in emergency room settings [26], and also in 1856. E-mail address: gduncan@med.unc.edu (G.E. Duncan). carefully controlled challenge studies [1,2,9,24,32,35,38]. 0006-8993 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. PII: S0006-8993(02)03156-6