title: NMDA receptors, cognition and schizophrenia--testing the validity of the NMDA receptor hypofunction hypothesis.
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, subchronic 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 pharmacokinetic-pharmacodynamic 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.
authors.affiliation: Eli Lilly and Co. Ltd., Lilly Research Centre, Erl Wood Manor, Sunninghill Road, Windlesham, Surrey GU20 6PH, UK. GILMOUR_GARY@LILLY.COM
authors.forename: Gary
authors.initials: G
authors.lastname: Gilmour
authors.forename: Sophie
authors.initials: S
authors.lastname: Dix
authors.forename: Laetitia
authors.initials: L
authors.lastname: Fellini
authors.forename: Francois
authors.initials: F
authors.lastname: Gastambide
authors.forename: Niels
authors.initials: N
authors.lastname: Plath
authors.forename: Thomas
authors.initials: T
authors.lastname: Steckler
authors.forename: John
authors.initials: J
authors.lastname: Talpos
authors.forename: Mark
authors.initials: M
authors.lastname: Tricklebank
mesh_terms: D000818:Animals; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015203:Reproducibility of Results; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate