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Published Online: 1 December 2010

Expression of Interneuron Markers in the Dorsolateral Prefrontal Cortex of the Developing Human and in Schizophrenia

Abstract

Objective:

The onset of schizophrenia symptoms in late adolescence implies a neurodevelopmental trajectory for the disease. Indeed, the γ-aminobutyric acid (GABA) inhibitory system shows protracted development, and GABA-ergic deficits are widely replicated in postmortem schizophrenia studies. The authors examined expression of several interneuron markers across postnatal human development and in schizophrenia to assess whether protracted development of certain interneuron subpopulations may be associated with a particular vulnerability in schizophrenia.

Method:

RNA was extracted postmortem from dorsolateral prefrontal cortex of individuals from age 6 weeks to 49 years (N=68) and from a cohort of normal comparison subjects and schizophrenia patients (N=74, 37 pairs). Expression levels of parvalbumin, cholecystokinin, somatostatin, neuropeptide Y, calretinin, calbindin, and vasoactive intestinal peptide were measured by quantitative reverse transcription-polymerase chain reaction. Changes in calretinin protein levels were examined by Western blot.

Results:

Interneuron marker genes followed one of three general expression profiles: either increasing (parvalbumin, cholecystokinin) or decreasing (somatostatin, calretinin, neuropeptide Y) in expression over postnatal life, with the most dramatic changes seen in the first few years before reaching a plateau; or increasing to peak expression in the toddler years before decreasing (calbindin, vasoactive intestinal peptide). mRNA expression of all genes, with the exception of calbindin (which increased), showed a reduction (8%-31%) in schizophrenia. Somatostatin showed the most dramatic reduction (31%) in schizophrenia.

Conclusions:

It appears that a heterogeneous population of interneurons is implicated in schizophrenia. Further studies are needed to determine whether specific interneuron subpopulations are altered or whether common or distinct upstream pathways are responsible for interneuron deficits in schizophrenia.

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Information & Authors

Information

Published In

Go to American Journal of Psychiatry
Go to American Journal of Psychiatry
American Journal of Psychiatry
Pages: 1479 - 1488
PubMed: 21041246

History

Received: 4 June 2009
Revision received: 2 November 2009
Revision received: 4 March 2010
Revision received: 27 April 2010
Revision received: 18 June 2010
Accepted: 15 July 2010
Published online: 1 December 2010
Published in print: December 2010

Authors

Details

Samantha J. Fung, Ph.D.
From the Schizophrenia Research Institute, Sydney, Australia; Neuroscience Research Australia, Sydney; the School of Medical Sciences and the School of Psychiatry, University of New South Wales; the Stanley Medical Research Institute, Rockville, Md.; and Elashoff Consulting, LLC, Redwood City, Calif.
Maree J. Webster, Ph.D.
From the Schizophrenia Research Institute, Sydney, Australia; Neuroscience Research Australia, Sydney; the School of Medical Sciences and the School of Psychiatry, University of New South Wales; the Stanley Medical Research Institute, Rockville, Md.; and Elashoff Consulting, LLC, Redwood City, Calif.
Sinthuja Sivagnanasundaram, Ph.D.
From the Schizophrenia Research Institute, Sydney, Australia; Neuroscience Research Australia, Sydney; the School of Medical Sciences and the School of Psychiatry, University of New South Wales; the Stanley Medical Research Institute, Rockville, Md.; and Elashoff Consulting, LLC, Redwood City, Calif.
Carlotta Duncan, Ph.D.
From the Schizophrenia Research Institute, Sydney, Australia; Neuroscience Research Australia, Sydney; the School of Medical Sciences and the School of Psychiatry, University of New South Wales; the Stanley Medical Research Institute, Rockville, Md.; and Elashoff Consulting, LLC, Redwood City, Calif.
Michael Elashoff, Ph.D.
From the Schizophrenia Research Institute, Sydney, Australia; Neuroscience Research Australia, Sydney; the School of Medical Sciences and the School of Psychiatry, University of New South Wales; the Stanley Medical Research Institute, Rockville, Md.; and Elashoff Consulting, LLC, Redwood City, Calif.
Cynthia Shannon Weickert, Ph.D.
From the Schizophrenia Research Institute, Sydney, Australia; Neuroscience Research Australia, Sydney; the School of Medical Sciences and the School of Psychiatry, University of New South Wales; the Stanley Medical Research Institute, Rockville, Md.; and Elashoff Consulting, LLC, Redwood City, Calif.

Notes

Address correspondence and reprint requests to Dr. Weickert, Neuroscience Research Australia, University of New South Wales, Corner of Barker and Easy St., Randwick, NSW 2031, Australia; [email protected] (e-mail).

Funding Information

The authors report no financial relationships with commercial interests.Supported by the Schizophrenia Research Institute with funding from the New South Wales Department of Health, the Macquarie Group Foundation, Neuroscience Research Australia, and University of New South Wales.The authors thank Shan Yuan Tsai and Duncan Sinclair for technical support. The authors acknowledge the assistance of Dr. H. Ronald Zielke and Robert Vigorito of the University of Maryland Brain and Tissue Bank for Developmental Disorders. Tissues were received from the Australian Brain Donor Programs New South Wales Tissue Resource Centre, which is supported by the University of Sydney, the National Health and Medical Research Council of Australia, the Schizophrenia Research Institute, the National Institute of Alcohol Abuse and Alcoholism, and the New South Wales Department of Health.

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