Article

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: 9.47). 10/2010; 69(1):63-70. DOI: 10.1016/j.biopsych.2010.08.020
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Cynthia Shannon Weickert, Dec 24, 2013
0 Followers
 · 
93 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Schizophrenia Research 10/2014; DOI:10.1016/j.schres.2014.10.020 · 4.43 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: 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.
    Schizophrenia Research 06/2014; 161(1). DOI:10.1016/j.schres.2014.04.041 · 4.43 Impact Factor
  • Source
    • "Importantly, the prefrontal cortex and medial temporal lobe (i.e., entorhinal cortex, ventral subiculum) stand out as the main regions affected in schizophrenia. In this respect several cytoarchitectural and neuronal morphometric abnormalities have been described at the level of the prefrontal cortex (Garey, 2010; Yang et al., 2011; Nesvåg et al., 2012; Palaniyappan and Liddle, 2012), the entorhinal cortex (Arnold, 2000; Falkai et al., 2000; Prasad et al., 2004) and the ventral subiculum (Arnold, 2000; Rosoklija et al., 2000; Law et al., 2004). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The psychic disintegration characteristic of schizophrenia is thought to result from a defective connectivity, of neurodevelopmental origin, between several integrative brain regions. The parahippocampal region and the prefrontal cortex are described as the main regions affected in schizophrenia. Interestingly, latent inhibition (LI) has been found to be reduced in patients with schizophrenia, and the existence of a dopaminergic dysfunction is also generally well accepted in this disorder. In the present review, we have integrated behavioral and neurochemical data obtained in a LI protocol involving adult rats subjected to neonatal functional inactivation of the entorhinal cortex, the ventral subiculum or the prefrontal cortex. The data discussed suggest a subtle and transient functional blockade during early development of the aforementioned brain regions is sufficient to induce schizophrenia-related behavioral and dopaminergic abnormalities in adulthood. In summary, these results support the view that our conceptual and methodological approach, based on functional disconnections, is valid for modeling some aspects of the pathophysiology of schizophrenia from a neurodevelopmental perspective.
    Frontiers in Behavioral Neuroscience 04/2014; 7:118. DOI:10.3389/fnbeh.2013.00118 · 4.16 Impact Factor
Show more