Increased density of microtubule associated protein 2-immunoreactive neurons in the prefrontal white matter of schizophrenic subjects

doi:10.1016/0920-9964(96)88521-5

Schizophrenia Research

Volume 19, Issues 2–3, May 1996, Pages 111-119

https://doi.org/10.1016/0920-9964(96)88521-5 Get rights and content

Abstract

Recent studies have suggested that schizophrenia may be related to prenatal disturbances in the cortical subplate, a transient but essential structure in the formation of cerebral cortical circuitry. Although most subplate neurons die during later development, some remain as the interstitial neurons of the adult white matter. In this study we used a monoclonal antibody against the cytoskeletal protein, microtubule associated protein-2 (MAP2), to quantify the density and distribution of labeled neurons in postmortem brain specimens containing the prefrontal white matter from five schizophrenic cases and matched controls. In both schizophrenics and matched controls, the density of white matter neurons decreased with increasing white matter depth. However, the mean density of MAP2-immunoreactive neurons was greater in the superficial white matter of the schizophrenic subjects compared to the matched controls. In contrast, no difference in the density of labeled neurons was seen in the deeper white matter. These findings are consistent with an abnormality in the development of the cortical subplate in at least some cases of schizophrenia.

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The most prominent transient compartment of the primate fetal cortex is the deep, cell-sparse, synapse-containing subplate compartment (SPC). The developmental role of the SPC and its extraordinary size in humans remain enigmatic.
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The subplate (SP) represents a transitory cytoarchitectural fetal compartment containing most subcortical and cortico-cortical afferents, and has a fundamental role in the structural development of the healthy adult brain. There is evidence that schizophrenia and autism may be determined by developmental defects in the cortex or cortical circuitry during the earliest stages of pregnancy. This article provides an overview on fetal SP development, considering its role in schizophrenia and autism, as supported by a systematic review of the main databases. The SP has been described as a cortical amplifier with a role in the coordination of cortical activity, and sensitive growth and migration windows have crucial consequences with respect to cognitive functioning. Although there are not enough studies to draw final conclusions, improved knowledge of the SP's role in schizophrenia and autism spectrum disorders may help to elucidate and possibly prevent the onset of these two severe disorders.
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Of the 13 studies reported, eight show an increase in IWMN density in the superficial white matter (Akbarian et al., 1996; Anderson et al., 1996; Connor et al., 2009; Eastwood and Harrison, 2003, 2005; Joshi et al., 2012; Kirkpatrick et al., 2003; Yang et al., 2011), three described changes in the deep white matter (Akbarian et al., 1993; Ikeda et al., 2004; Rioux et al., 2003), and two reported no changes (Beasley et al., 2002; Molnar et al., 2003) in IWMN density below the cortex in postmortem brains in schizophrenia. This work has focussed largely on IWMN density in frontal brain regions implicated in schizophrenia, including the dorsolateral prefrontal cortex (Akbarian et al., 1993, 1996; Anderson et al., 1996; Eastwood and Harrison, 2003, 2005; Yang et al., 2011), orbitofrontal cortex (Joshi et al., 2012) and anterior cingulate white matter (Connor et al., 2009). All five studies utilising neuronal nuclei protein (NeuN) to identify IWMNs reported increased density in the brains of schizophrenia subjects (Connor et al., 2009; Eastwood and Harrison, 2003, 2005; Joshi et al., 2012; Yang et al., 2011).
Interstitial neurons are located among white matter tracts of the human and rodent brain. Post-mortem studies have identified increased interstitial white matter neuron (IWMN) density in the fibre tracts below the cortex in people with schizophrenia. The current study assesses IWMN pathology in a model of maternal immune activation (MIA); a risk factor for schizophrenia. Experimental MIA was produced by an injection of polyinosinic:polycytidylic acid (PolyI:C) into pregnant rats on gestational day (GD) 10 or GD19. A separate control group received saline injections. The density of neuronal nuclear antigen (NeuN⁺) and somatostatin (SST⁺) IWMNs was determined in the white matter of the corpus callosum in two rostrocaudally adjacent areas in the 12 week old offspring of GD10 (n = 10) or GD19 polyI:C dams (n = 18) compared to controls (n = 20). NeuN⁺ IWMN density trended to be higher in offspring from dams exposed to polyI:C at GD19, but not GD10. A subpopulation of these NeuN⁺ IWMNs was shown to express SST. PolyI:C treatment of dams induced a significant increase in the density of SST⁺ IWMNs in the offspring when delivered at both gestational stages with more regionally widespread effects observed at GD19. A positive correlation was observed between NeuN⁺ and SST⁺ IWMN density in animals exposed to polyI:C at GD19, but not controls. This is the first study to show that MIA increases IWMN density in adult offspring in a similar manner to that seen in the brain in schizophrenia. This suggests the MIA model will be useful in future studies aimed at probing the relationship between IWMNs and schizophrenia.
NeuN<sup>+</sup> neuronal nuclei in non-human primate prefrontal cortex and subcortical white matter after clozapine exposure
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Citation Excerpt :
Our results strongly suggest that clozapine-induced changes in cell type-specific phenotypic marker expression could occur independently of, or at least prior to any ensuing losses in brain regional volumes or tissue mass. Finally, as mentioned already above, the findings presented here warrant at least a partial reinterpretation of the 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). These alterations, which may be more prominent in subjects diagnosed with deficit syndrome and negative symptoms (Kirkpatrick et al., 2003), have been hitherto primarily interpretated as evidence for defective neurodevelopment (Kostovic et al., 2011).
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 6 months 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.
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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.
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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.
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.
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.
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Increased density of microtubule associated protein 2-immunoreactive neurons in the prefrontal white matter of schizophrenic subjects

Abstract

Psychiatry Res.

Biol. Psychiatry

Biol. Psychiatry

Altered distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase cells in frontal lobe of schizophrenics implies disturbances of cortical development

Arch. Gen. Psychiatry

Distorted distribution of nicotinamide-adenine dinucleotide phosphate-diaphorase neurons in temporal lobe of schizophrenics implies anomalous cortical development

Arch. Gen. Psychiatry

Gene expression for glutamic acid decarboxylase is reduced without loss of neurons in prefrontal cortex of schizophrenics

Arch. Gen. Psychiatry

The subplate, a transient neocortical structure: Its role in the development of connections between thalamus and cortex

Abnormal expression of two microtubule-associated proteins (MAP2 and MAP5) in specific subfields of the hippocampal formation in schizophrenia

Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients

Arch. Gen. Psychiatry

Advancing a neurodevelopmental origin for schizophrenia

Arch. Gen. Psychiatry

Brain morphology and schizophrenia: A magnetic resonance imaging study of limbic, prefrontal cortex, and caudate structures

Arch. Gen. Psychiatry

Frontrostriatal disorder of cerebral metabolism in never-medicated schizophrenics

Arch. Gen. Psychiatry

Interstitial cells of the adult neocortical white matter are the remnant of the early generated subplate neuron population

J. Comp. Neurol.

Involvement of subplate neurons in the formation of ocular dominance columns

Science

Segregation of geniculocortical afferents during the critical period: A role for subplate neurons

J. Neurosci.

Requirement for subplate neurons in the formation of thalamocortical connections

Nature

Further evidence for dementia of the prefrontal type in schizophrenia?

Arch. Gen. Psychiatry

Nonphosphorylated neurofilament protein and calbindin immunoreactivity in layer III pyramidal neurons of human neocortex

Cereb. Cortex