Preprint Review Version 1 Preserved in Portico This version is not peer-reviewed

Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia

Version 1 : Received: 15 May 2023 / Approved: 16 May 2023 / Online: 16 May 2023 (03:06:00 CEST)

A peer-reviewed article of this Preprint also exists.

Vinnakota, C.; Hudson, M.R.; Jones, N.C.; Sundram, S.; Hill, R.A. Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia. Int. J. Mol. Sci. 2023, 24, 11835. Vinnakota, C.; Hudson, M.R.; Jones, N.C.; Sundram, S.; Hill, R.A. Potential Roles for the GluN2D NMDA Receptor Subunit in Schizophrenia. Int. J. Mol. Sci. 2023, 24, 11835.

Abstract

Glutamate NMDA receptor (NMDAR) hypofunction has been proposed to underlie schizophrenia symptoms because administration of NMDAR antagonists reproduces behavioral and molecular schizophrenia-like phenotypes in healthy humans and animal models. However, the role of specific NMDAR subunits in these schizophrenia-relevant characteristics is largely unknown. Mounting evidence implicates the GluN2D subunit of NMDAR in some of these symptoms and pathology. Firstly, genetic and post-mortem studies show changes in the GluN2D subunit in people with schizophrenia. Secondly, the psychosis-inducing effects of NMDAR antagonists are blunted in GluN2D-knockout mice, suggesting that the GluN2D subunit mediates NMDAR antagonist-induced psychotomimetic effects. Thirdly, in the mature brain, the GluN2D subunit is relatively enriched in parvalbumin (PV)-containing interneurons, a cell type hypothesized to underlie the cognitive symptoms of schizophrenia. Lastly, the GluN2D subunit is widely and abundantly expressed early in development which could be of importance considering schizophrenia is a disorder that has its origins in early neurodevelopment. The limitations of currently available therapies warrant further research into novel therapeutic targets such as the GluN2D subunit which may help us better understand underlying disease mechanisms and develop novel and more effective treatment options.

Keywords

GluN2D; Schizophrenia; NMDA receptor; NMDAR antagonists

Subject

Medicine and Pharmacology, Neuroscience and Neurology

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