A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

A postmortem analysis of NMDA ionotropic and group 1 metabotropic glutamate receptors in the nucleus accumbens in schizophrenia

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J Psychiatry Neurosci 2018;43(2):102-110

Jeremy S. Lum, BMedHlthSc Hons; Samuel J. Millard, BMedHlthSc Hons; Xu-Feng Huang, PhD; Lezanne Ooi, PhD; Kelly A. Newell, PhD

Abstract

Background: The nucleus accumbens (NAcc) has been implicated in the pathology and treatment of schizophrenia. Recent postmortem evidence suggests a hyperglutamatergic state in the NAcc. With the present study we aimed to explore possible glutamatergic alterations in the NAcc of a large schizophrenia cohort.

Methods: We performed immunoblots on postmortem NAcc samples from 30 individuals who had schizophrenia and 30 matched controls. We examined the protein expression of primary glutamatergic receptors, including the N-methyl-ᴅ-aspartate (NMDA) receptor (NR1, NR2A and NR2B subunits) and the group 1 metabotropic glutamate receptor (mGluR1 and mGluR5; dimeric and monomeric forms). In addition, we measured the group 1 mGluR endogenous regulators, neurochondrin and Homer1b/c, which have recently been implicated in the pathophysiology of schizophrenia.

Results: Protein levels of glutamatergic receptors and endogenous regulators were not significantly different between the controls and individuals who had schizophrenia. Furthermore, mGluR5, but not mGluR1, showed a positive association with NMDA receptor subunits, suggesting differential interactions between these receptors in this brain region.

Limitations: Investigation of these proteins in antipsychotic-naive individuals, in addition to the subregions of the NAcc and subcellular fractions, will strengthen future studies.

Conclusion: The present study does not provide evidence for glutamatergic abnormalities within the NAcc of individuals with schizophrenia. Taken together with the results of previous studies, these findings suggest NMDA receptors and group 1 mGluRs are altered in a brain region–dependent manner in individuals with schizophrenia. The differential associations between mGluR1, mGluR5 and NMDA receptors observed in this study warrant further research into the interactions of these proteins and the implications for the therapeutic and adverse effect profile of glutamatergic-based novel therapeutics.


Submitted Apr. 13, 2017; Revised July 8, 2017; Accepted July 16, 2017; Online first Oct. 10, 2017

Acknowledgments: This work was supported by the Schizophrenia Research Institute utilising infrastructure funding from the NSW Ministry of Health in the form of an A.M Woods Scholarship awarded to J.S. Lum. J.S. Lum is supported by Australian Rotary Health in the form of an Ian Scott Scholarship. This research has been conducted with the support of the Australian Government Research Training Program Scholarship awarded to J.S. Lum and S.J. Millard. Postmortem brain tissues were received from the NSW Tissue Resource Centre, which is supported by the National Health and Medical Research Council of Australia, Schizophrenia Research Institute and the National Institute of Alcohol Abuse and Alcoholism (NIH (NIAA) R24AA012725). This research was supported by the Schizophrenia Fellowship of NSW in the form of a Peter Meyer Fund Grant to K.A. Newell. L. Ooi is supported by a National Health and Medical Research Council (NHMRC) of Australia Fellowship (APP1135720).

Affiliations: From the School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia (Lum, Millard, Huang, Newell); the Illawarra Health and Medical Research Institute, Wollongong, New South Wales, Australia (Lum, Millard, Huang, Ooi, Newell); the Schizophrenia Research Institute, Darlinghurst, New South Wales, Australia (Lum); and the School of Biological Sciences, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales, Australia (Ooi).

Competing interests: None declared.

Contributors: J.S. Lum and K.A. Newell designed the study. J.S. Lum, S.J. Millard and K.A. Newell acquired the data, which all authors analyzed. J.S. Lum and K.A. Newell wrote the article, which all authors critically reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.

DOI: 10.1503/jpn.170077

Correspondence to: K.A. Newell, School of Medicine, Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, New South Wales 2522 Australia; knewell@uow.edu.au