Increased Interstitial White Matter Neuron Density in the Dorsolateral Prefrontal Cortex of People with Schizophrenia

Schizophrenia Research Institute, University of New South Wales, Sydney, Australia.
Biological psychiatry (Impact Factor: 10.26). 10/2010; 69(1):63-70. DOI: 10.1016/j.biopsych.2010.08.020
Source: PubMed


Interstitial white matter neurons (IWMNs) may reflect immature neurons that migrate tangentially to the neocortex from the ganglionic eminence to form cortical interneurons. Alterations of interneuron markers have been detected in gray matter of dorsolateral prefrontal cortex in schizophrenia, and IWMNs are also reported to be altered in schizophrenia. In this study, we considered whether a potential link exists between these two pathological findings.
From a cohort of 29 schizophrenia subjects and 37 control subjects, IWMN densities were determined in the dorsolateral prefrontal cortex by counting neuronal nuclear antigen (NeuN) and somatostatin (SST)-positive cells. Double-label immunofluorescence was carried out to determine the overlap between SST+/NeuN+ and SST+/neuropeptide Y + neurons.
We found that density of NeuN + IWMNs in superficial white matter is significantly increased in schizophrenia subjects compared with control subjects. There was a significant negative correlation between SST mRNA expression in gray matter and NeuN + IWMN density. In schizophrenic patients with increased NeuN IWMN density, the density of SST-expressing neurons in white matter was also higher compared with control subjects. A subpopulation of SST immunopositive cells also show coexpression of neuropeptide Y.
Our study confirmed previous results indicating that the density of NeuN + IWMNs is increased in superficial white matter in schizophrenia. We provide the first evidence that increased IWMN density correlates with a gray matter interneuron deficit, suggesting that migration of interneurons from white matter to the cortex may be deficient in some patients with schizophrenia, consistent with an interneuron deficit in schizophrenia.

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Available from: Cynthia Shannon Weickert, Dec 24, 2013
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    • "The large majority of WMN are considered remnants of the subplate, a transient structure important for connectivity formation during early development (Kanold, 2004; Kostovic et al., 2011). Interestingly, more than 15 studies have examined postmortem brain tissue and reported supernormal WMN numbers and densities in prefrontal, cingulate and medial or lateral temporal cortex of subjects diagnosed with schizophrenia (Akbarian et al., 1993a; Akbarian et al., 1996; Akbarian et al., 1993b; Anderson et al., 1996; Eastwood and Harrison, 2003, 2005; Ikeda et al., 2004; Joshi et al., 2012; Kirkpatrick et al., 1999; Kirkpatrick et al., 2003; Rioux et al., 2003; Yang et al., 2011). While negative findings have also been pub - lished ( Beasley et al . "
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    ABSTRACT: Increased neuronal densities in subcortical white matter have been reported for some cases with schizophrenia. The underlying cellular and molecular mechanisms remain unresolved. We exposed 26 young adult macaque monkeys for 6months to either clozapine, haloperidol or placebo and measured by structural MRI frontal gray and white matter volumes before and after treatment, followed by observer-independent, flow-cytometry-based quantification of neuronal and non-neuronal nuclei and molecular fingerprinting of cell-type specific transcripts. After clozapine exposure, the proportion of nuclei expressing the neuronal marker NeuN increased by approximately 50% in subcortical white matter, in conjunction with a more subtle and non-significant increase in overlying gray matter. Numbers and proportions of nuclei expressing the oligodendrocyte lineage marker, OLIG2, and cell-type specific RNA expression patterns, were maintained after antipsychotic drug exposure. Frontal lobe gray and white matter volumes remained indistinguishable between antipsychotic-drug-exposed and control groups. Chronic clozapine exposure increases the proportion of NeuN(+) nuclei in frontal subcortical white matter, without alterations in frontal lobe volumes or cell type-specific gene expression. Further exploration of neurochemical plasticity in non-human primate brain exposed to antipsychotic drugs is warranted.
    Full-text · Article · Jan 2016 · Schizophrenia Research
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    • "could be related to neurodevelopmental alterations (Benes, 2012), including the excessive numbers and densities of subcortical white matter neurons that seem to affect some cases with SCZ (Akbarian et al., 1993a, b, 1995; Anderson et al., 1996; Kirkpatrick et al., 1999; Rioux et al., 2003; Eastwood and Harrison, 2005; Yang et al., 2011; Benes, 2012; Joshi et al., 2012). However, the circuitry model with the greatest impact in the field to date was put forward by Lewis et al. (2005). "
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    ABSTRACT: Expression of GAD1 GABA synthesis enzyme is highly regulated by neuronal activity and reaches mature levels in the prefrontal cortex not before adolescence. A significant portion of cases diagnosed with schizophrenia show deficits in GAD1 RNA and protein levels in multiple areas of adult cerebral cortex, possibly reflecting molecular or cellular defects in subtypes of GABAergic interneurons essential for network synchronization and cognition. Here, we review 20 years of progress towards a better understanding of disease-related regulation of GAD1 gene expression. For example, deficits in cortical GAD1 RNA in some cases of schizophrenia are associated with changes in the epigenetic architecture of the promoter, affecting DNA methylation patterns and nucleosomal histone modifications. These localized chromatin defects at the 5′ end of GAD1 are superimposed by disordered locus-specific chromosomal conformations, including weakening of long-range promoter-enhancer loopings and physical disconnection of GAD1 core promoter sequences from cis-regulatory elements positioned 50 kilobases further upstream. Studies on the 3-dimensional architecture of the GAD1 locus in neurons, including developmentally regulated higher order chromatin compromised by the disease process, together with exploration of locus-specific epigenetic interventions in animal models, could pave the way for future treatments of psychosis and schizophrenia.
    Full-text · Article · Oct 2014 · Schizophrenia Research
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    • "An increased density of interstitial white matter neurons, one of the more consistent pathological abnormalities found in schizophrenia (Anderson et al., 1996; Eastwood and Harrison, 2003; Kirkpatrick et al., 2003; Eastwood and Harrison, 2005; Connor et al., 2011; Yang et al., 2011) (recently reviewed by Connor et al. (2011)), further supports the hypothesis that neuroinflammation precedes white matter pathology in schizophrenia. One putative mechanism of increased white matter neuronal density in human disease involves entrapment of neurons migrating from the germinal matrix to the cortex due to inflammation-induced early white matter injury (Rousset et al., 2006; Leviton and Gressens, 2007). "
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    ABSTRACT: Background: Neuroinflammation and white matter pathology have each been independently associated with schizophrenia, and experimental studies have revealed mechanisms by which the two can interact in vitro, but whether these abnormalities simultaneously co-occur in people with schizophrenia remains unclear. Method: We searched MEDLINE, EMBASE, PsycINFO and Web of Science from inception through 12 January 2014 for studies reporting human data on the relationship between microglial or astroglial activation, or cytokines and white matter pathology in schizophrenia. Results: Fifteen studies totaling 792 subjects (350 with schizophrenia, 346 controls, 49 with bipolar disorder, 37 with major depressive disorder and 10 with Alzheimer's disease) met all eligibility criteria. Five neuropathological and two neuroimaging studies collectively yielded consistent evidence of an association between schizophrenia and microglial activation, particularly in white rather than gray matter regions. Ultrastructural analysis revealed activated microglia near dystrophic and apoptotic oligodendroglia, demyelinating and dysmyelinating axons and swollen and vacuolated astroglia in subjects with schizophrenia but not controls. Two neuroimaging studies found an association between carrier status for a functional single nucleotide polymorphism in the interleukin-1β gene and abnormal white as well as gray matter volumes in schizophrenia but not controls. A neuropathological study found that orbitofrontal white matter neuronal density was increased in schizophrenia cases exhibiting high transcription levels of pro-inflammatory cytokines relative to those exhibiting low transcription levels and to controls. Schizophrenia was associated with decreased astroglial density specifically in subgenual cingulate white matter and anterior corpus callosum, but not other gray or white matter areas. Astrogliosis was consistently absent. Data on astroglial gene expression, mRNA expression and protein concentration were inconsistent. Conclusion: Neuroinflammation is associated with white matter pathology in people with schizophrenia, and may contribute to structural and functional disconnectivity, even at the first episode of psychosis.
    Full-text · Article · Jun 2014 · Schizophrenia Research
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