Invited review NMDA receptors, cognition and schizophrenia e Testing the validity of the NMDA receptor hypofunction hypothesis q Gary Gilmour a, * , Sophie Dix a , Laetitia Fellini b , Francois Gastambide a , Niels Plath c , Thomas Steckler b , John Talpos b , Mark Tricklebank a a Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK b Janssen Pharmaceutica NV, Turnhoutseweg 30, 2340 Beerse, Belgium c Synaptic Transmission 1, H. Lundbeck A/S, 2500 Valby, Denmark article info Article history: Received 14 December 2010 Received in revised form 10 March 2011 Accepted 12 March 2011 Keywords: Schizophrenia Cognition NMDA Translation Validity Rats Humans abstract Cognitive dysfunction is core to schizophrenia, and remains poorly treated by existing therapies. A prominent hypothesis suggests that many symptoms arise from N-methyl-D-aspartate receptor (NMDAR) hypofunction. Subsequently, there has emerged a widespread use of many preclinical and clinical NMDAR antagonist models in the search for novel treatments. Clinically, ketamine is broadly purported to induce cognitive symptoms similar to those of schizophrenia. Preclinically, acute, sub- chronic and neonatal NMDAR antagonist administration models are all utilised in this context, as well as NMDAR transgenic animals. In this review, key strengths and weaknesses of each of these approaches are described with regard to their ability to recapitulate the deficits seen in patients. Given the breadth of literature and vogue for research in this topic, instances of NMDAR antagonist effects in the desired domains can readily be found preclinically. However, it is surprisingly difficult to identify any single aspect of cognitive function that possesses complete translational integrity. That is, there does not seem to be an NMDAR antagonist regimen proven to engage NMDARs equivalently in humans and animals that reliably produces the same cognitive effects in each species. This is likely due to the diverse range of techniques and models used by preclinical researchers, a paucity of research describing pharmacoki- neticepharmacodynamic relationships of NMDAR antagonist regimens, little capability to measure target engagement, and the lack of harmonized procedures between preclinical and clinical studies. Realizing the potential of the NMDAR hypofunction hypothesis to model cognitive impairment in schizophrenia will require some of these issues to be addressed. This article is part of a Special Issue entitled ‘Schizophrenia’. Ó 2011 Elsevier Ltd. All rights reserved. 1. Cognitive dysfunction in schizophrenia Impaired cognition is increasingly recognized as a core feature of schizophrenia and is thought to be intrinsic to its pathogenesis (Elvevag and Goldberg, 2000). Cognitive impairments often precede the first psychotic episode (Erlenmeyer-Kimling et al., 2000), are stable over time (Albus et al., 2002; Reichenberg et al., 2010) and strongly correlate with functional outcome (Green et al., 2000; Green and Nuechterlein, 2004). Existing therapies do not treat these aspects of the disease adequately, in part reflecting the generalized nature of schizophrenic deficits which span several neuropsychological domains (Heinrichs and Zakzanis, 1998). Consequently, initiatives like Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) (Green et al., 2004a,b) and its descendant Cognitive Neuroscience Treat- ment Research to Improve Cognition in Schizophrenia (CNTRICS) (Barch et al., 2009) have been established to help focus and guide research in this context. MATRICS and CNTRICS identify several broad cognitive domains as commonly altered in schizophrenic patients: attention/vigilance; speed of processing; working memory; learning and memory; executive control and social/ emotional cognition (Nuechterlein et al., 2004; Barch et al., 2009). Abbreviations: HV, human volunteer; NMDA, N-methyl-D-aspartate; NMDAR, N- methyl-D-aspartate receptor; PCP, phencyclidine. q Source of funding: The NEWMEDS project is funded by the Innovative Medi- cines Initiative Joint Undertaking (IMI JU). A publiceprivate partnership between the pharmaceutical industry (represented by the European Federation of Pharma- ceutical Industries and Associations, EFPIA) and the European Union (represented by the European Commission). * Corresponding author. E-mail address: GILMOUR_GARY@LILLY.COM (G. Gilmour). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2011.03.015 Neuropharmacology 62 (2012) 1401e1412