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High White Matter Neuron Density with Elevated Cortical Cytokine Expression in Schizophrenia

  • Samantha J. Fung
    Correspondence
    Corresponding author
    Affiliations
    Schizophrenia Research Institute, University of New South Wales, Randwick, Australia

    Neuroscience Research Australia, University of New South Wales, Randwick, Australia

    School of Psychiatry, University of New South Wales, Randwick, Australia
    Search for articles by this author
  • Dipesh Joshi
    Affiliations
    Schizophrenia Research Institute, University of New South Wales, Randwick, Australia

    Neuroscience Research Australia, University of New South Wales, Randwick, Australia

    School of Psychiatry, University of New South Wales, Randwick, Australia
    Search for articles by this author
  • Stu G. Fillman
    Affiliations
    Schizophrenia Research Institute, University of New South Wales, Randwick, Australia

    Neuroscience Research Australia, University of New South Wales, Randwick, Australia

    School of Psychiatry, University of New South Wales, Randwick, Australia
    Search for articles by this author
  • Cynthia Shannon Weickert
    Affiliations
    Schizophrenia Research Institute, University of New South Wales, Randwick, Australia

    Neuroscience Research Australia, University of New South Wales, Randwick, Australia

    School of Psychiatry, University of New South Wales, Randwick, Australia
    Search for articles by this author
      While the primary etiology of schizophrenia remains elusive, deficient cortical inhibitory circuitry appears to play an important role in the disease. Many postmortem studies implicate gamma-aminobutyric acid (GABA)ergic interneurons in schizophrenia through reduced expression of glutamic acid decarboxylase (GAD67), parvalbumin, somatostatin, and other biochemical markers of interneurons (
      • Akbarian S.
      • Kim J.J.
      • Potkin S.G.
      • Hagman J.O.
      • Tafazzoli A.
      • Bunney Jr, W.E.
      • et al.
      Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics.
      ,
      • Fung S.J.
      • Webster M.J.
      • Sivagnanasundaram S.
      • Duncan C.
      • Elashoff M.
      • Weickert C.S.
      Expression of interneuron markers in the dorsolateral prefrontal cortex of the developing human and in schizophrenia.
      ,
      • Hashimoto T.
      • Arion D.
      • Unger T.
      • Maldonado-Aviles J.G.
      • Morris H.M.
      • Volk D.W.
      • et al.
      Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia.
      ,
      • Hashimoto T.
      • Bazmi H.H.
      • Mirnics K.
      • Wu Q.
      • Sampson A.R.
      • Lewis D.A.
      Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia.
      ,
      • Hashimoto T.
      • Volk D.W.
      • Eggan S.M.
      • Mirnics K.
      • Pierri J.N.
      • Sun Z.
      • et al.
      Gene expression deficits in a subclass of GABA neurons in the prefrontal cortex of subjects with schizophrenia.
      ,
      • Morris H.M.
      • Hashimoto T.
      • Lewis D.A.
      Alterations in somatostatin mRNA expression in the dorsolateral prefrontal cortex of subjects with schizophrenia or schizoaffective disorder.
      ,
      • Volk D.W.
      • Austin M.C.
      • Pierri J.N.
      • Sampson A.R.
      • Lewis D.A.
      Decreased glutamic acid decarboxylase67 messenger RNA expression in a subset of prefrontal cortical gamma-aminobutyric acid neurons in subjects with schizophrenia.
      ). In addition, at the physiological level, aberrant gamma-band oscillations, thought to be regulated by a subset of interneurons (
      • Sohal V.S.
      • Zhang F.
      • Yizhar O.
      • Deisseroth K.
      Parvalbumin neurons and gamma rhythms enhance cortical circuit performance.
      ), are altered in schizophrenia (
      • Uhlhaas P.J.
      • Singer W.
      Abnormal neural oscillations and synchrony in schizophrenia.
      ). Our previous publications indicate that deficits in cortical GABAergic markers in the gray matter are correlated with increased density of neurons in underlying white matter (
      • Joshi D.
      • Fung S.J.
      • Rothwell A.
      • Shannon Weickert C.
      Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia.
      ,
      • Yang Y.
      • Fung S.J.
      • Rothwell A.
      • Tianmei S.
      • Weickert C.S.
      Increased interstitial white matter neuron density in the dorsolateral prefrontal cortex of people with schizophrenia.
      ) and that the majority (~80%) of white matter neurons express GAD65/67 (
      • Joshi D.
      • Fung S.J.
      • Rothwell A.
      • Shannon Weickert C.
      Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia.
      ). Increases in white matter neuron density in schizophrenia have previously been reported (
      • Akbarian S.
      • Bunney Jr, W.E.
      • Potkin S.G.
      • Wigal S.B.
      • Hagman J.O.
      • Sandman C.A.
      • et al.
      Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development.
      ,
      • Anderson S.A.
      • Volk D.W.
      • Lewis D.A.
      Increased density of microtubule associated protein 2-immunoreactive neurons in the prefrontal white matter of schizophrenic subjects.
      ,
      • Eastwood S.L.
      • Harrison P.J.
      Interstitial white matter neurons express less reelin and are abnormally distributed in schizophrenia: Towards an integration of molecular and morphologic aspects of the neurodevelopmental hypothesis.
      ,
      • Eastwood S.L.
      • Harrison P.J.
      Interstitial white matter neuron density in the dorsolateral prefrontal cortex and parahippocampal gyrus in schizophrenia.
      ,
      • Kirkpatrick B.
      • Messias N.C.
      • Conley R.R.
      • Roberts R.C.
      Interstitial cells of the white matter in the dorsolateral prefrontal cortex in deficit and nondeficit schizophrenia.
      ) and interpreted in terms of aberrant developmental events: lack of programmed cell death of subplate cells, or arrested/retarded migration of neurons to the cortex in early development. Our previous interpretation of our data relating reduced GABA markers with increased white matter neuron density was consistent with this latter view (
      • Joshi D.
      • Fung S.J.
      • Rothwell A.
      • Shannon Weickert C.
      Higher gamma-aminobutyric acid neuron density in the white matter of orbital frontal cortex in schizophrenia.
      ,
      • Yang Y.
      • Fung S.J.
      • Rothwell A.
      • Tianmei S.
      • Weickert C.S.
      Increased interstitial white matter neuron density in the dorsolateral prefrontal cortex of people with schizophrenia.
      ) and gains support from the involvement of several candidate schizophrenia genes (e.g., neuregulin, DISC1, reelin) in regulating neuronal migration during development (
      • Impagnatiello F.
      • Guidotti A.R.
      • Pesold C.
      • Dwivedi Y.
      • Caruncho H.
      • Pisu M.G.
      • et al.
      A decrease of reelin expression as a putative vulnerability factor in schizophrenia.
      ,
      • Millar J.K.
      • Wilson-Annan J.C.
      • Anderson S.
      • Christie S.
      • Taylor M.S.
      • Semple C.A.
      • et al.
      Disruption of two novel genes by a translocation co-segregating with schizophrenia.
      ,
      • Stefansson H.
      • Sigurdsson E.
      • Steinthorsdottir V.
      • Bjornsdottir S.
      • Sigmundsson T.
      • Ghosh S.
      • et al.
      Neuregulin 1 and susceptibility to schizophrenia.
      ). However, our recent findings regarding elevated neuroinflammation in the cortex of schizophrenia subjects could call for a need to further consider what increases in white matter neuron density in schizophrenia may mean.
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