title: Knockout of NMDA-receptors from parvalbumin interneurons sensitizes to schizophrenia-related deficits induced by MK-801.
abstract: It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1(ΔPV) mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1(ΔPV) mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1(ΔPV)mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1(ΔPV)mice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1(ΔPV)mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: A M
authors.initials: AM
authors.lastname: Bygrave
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Masiulis
authors.affiliation: Institute of Neurology, University College London, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Nicholson
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.|Department of Psychology, University of Landau, Landau, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Berkemann
authors.affiliation: Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: C
authors.initials: C
authors.lastname: Barkus
authors.affiliation: Max-Planck Institute for Medical Research, Heidelberg, Germany.
authors.forename: R
authors.identifier: http://orcid.org/0000-0003-3370-0970
authors.initials: R
authors.lastname: Sprengel
authors.affiliation: Department of Psychiatry, University of Oxford, and Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Harrison
authors.affiliation: Institute of Neurology, University College London, London, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Kullmann
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Bannerman
authors.affiliation: Department of Experimental Psychology, University of Oxford, Oxford, UK.|Institute of Neurology, University College London, London, UK.|Institute of Applied Physiology, Ulm University, Ulm, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kätzel
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate; D005260:Female; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010320:Parvalbumins / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000139:chemically induced / Q000503:physiopathology*
chemical_list: D010320:Parvalbumins; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate