Higher Gamma-Aminobutyric Acid Neuron Density in the White Matter of Orbital Frontal Cortex in Schizophrenia

  • Dipesh Joshi
    Address correspondence to Dipesh Joshi, Ph.D., Schizophrenia Research Laboratory, Neuroscience Research Australia, Hospital Road, Randwick, NSW 2031, Australia
    Schizophrenia Research Institute, Sydney, Australia

    Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, Australia

    School of Psychiatry, University of New South Wales, Sydney, Australia
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  • Samantha J. Fung
    Schizophrenia Research Institute, Sydney, Australia

    Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, Australia

    School of Psychiatry, University of New South Wales, Sydney, Australia
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  • Alice Rothwell
    Schizophrenia Research Institute, Sydney, Australia

    Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, Australia
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  • Cynthia Shannon Weickert
    Schizophrenia Research Institute, Sydney, Australia

    Schizophrenia Research Laboratory, Neuroscience Research Australia, Randwick, Australia

    School of Psychiatry, University of New South Wales, Sydney, Australia
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      In the orbitofrontal cortex (OFC), reduced gray matter volume and reduced glutamic acid decarboxylase 67kDa isoform (GAD67) messenger (m)RNA are found in schizophrenia; however, how these alterations relate to developmental pathology of interneurons is unclear. The present study therefore aimed to determine if increased interstitial white matter neuron (IWMN) density exists in the OFC; whether gamma-aminobutyric acid (GABA)ergic neuron density in OFC white matter was altered; and how IWMN density may be related to an early-expressed inhibitory neuron marker, Dlx1, in OFC gray matter in schizophrenia.


      IWMN densities were determined (38 schizophrenia and 38 control subjects) for neuronal nuclear antigen (NeuN+) and 65/67 kDa isoform of glutamic acid decarboxylase immunopositive (GAD65/67+) neurons. In situ hybridization was performed to determine Dlx1 and GAD67 mRNA expression in the OFC gray matter.


      NeuN and GAD65/67 immunopositive cell density was significantly increased in the superficial white matter in schizophrenia. Gray matter Dlx1 and GAD67 mRNA expression were reduced in schizophrenia. Dlx1 mRNA levels were negatively correlated with GAD65/67 IWMN density.


      Our study provides evidence that pathology of IWMNs in schizophrenia includes GABAergic interneurons and that increased IWMN density may be related to GABAergic deficits in the overlying gray matter. These findings provide evidence at the cellular level that the OFC is a site of pathology in schizophrenia and support the hypothesis that inappropriate migration of cortical inhibitory interneurons occurs in schizophrenia.

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      • A New Paradigm for Understanding Gamma-Aminobutyric Acid Cell Pathology in Schizophrenia?
        Biological PsychiatryVol. 72Issue 9
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          The article by Joshi et al. (1) in this edition of Biological Psychiatry is a provocative study that addresses a long-standing question as to whether gamma-aminobutyric acid (GABA) cell pathology in schizophrenia can be understood within a neurodevelopmental framework. Following initial reports that GABA cells are reduced in number and function in superficial cortical layers in schizophrenics, it was suggested that these changes may be related to disturbed migration during prenatal and early postnatal development (2).
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