Research ReportAssociation between myelin basic protein expression and left entorhinal cortex pre-alpha cell layer disorganization in schizophrenia
Introduction
Schizophrenia is a chronic, debilitating psychiatric disorder with unclear pathogenesis, outlined by the additive effect of multiple susceptibility genes interacting with environmental factors. Whatever the fundamental causes of schizophrenia, it seems that their influences are exerted from early in life, supporting a neurodevelopmental origin of the disorder (Weinberger, 1996, Lewis and Levitt, 2002). Brain-structural abnormalities are present in first-episode, drug-naïve patients. Some of them exist before the onset of psychosis and occur in at risk and unaffected relatives of schizophrenia patients [(Zipursky et al., 1998, Gur et al., 1999, Szeszko et al., 2003), reviewed in (Harrison and Weinberger, 2005)].
It is widely accepted that schizophrenia does not have characteristics of a neurodegenerative disorder such as gliosis (Falkai et al., 1999). Still, evidence for “neurodegeneration without gliosis” exists. Namely, the pathological processes in schizophrenia could be interpreted as an arrest of the developmental process of myelination (Bartzokis, 2002). White matter myelination plays a crucial role in rapid impulse conduction and also supports the brain's structural synchrony. Abnormal connectivity is regarded as a central abnormality in schizophrenia. Magnetic resonance imaging (MRI) studies first revealed volume reductions in cortical white matter in schizophrenia. Newer scanning techniques, namely magnetic transfer imaging (MTI) and diffusion tensor imaging (DTI), showed decrease in the myelin or axonal membrane in cortical regions and decreased white matter anisotropy (a measurement of the coherence along white matter tracts), respectively [reviewed in (Davis et al., 2003)]. In the entorhinal cortex (ERC), a combined high-resolution MRI and DTI study showed decreased volumes of the ERC and reduction of diffusional anisotropy, suggesting disturbed connectivity to the hippocampus (Kalus et al., 2005).
Direct investigation of post-mortem tissue showed structural abnormalities of myelin sheath and regressive changes in oligodendrocytes in the prefrontal cortex (PFC) and CA3 subregion of the hippocampus, suggesting apoptotic or necrotic cell death [(Kolomeets and Uranova, 2008), reviewed in (Davis et al., 2003)]. Additionally the number of oligodendrocytes was reduced in the PFC (Hof et al., 2002, Uranova et al., 2004, Uranova et al., 2007) as well as in the CA4 subregion of hippocampus (Schmitt et al., 2009). Reduced number, abnormalities in or death of oligodendrocytes readily influence or harm myelin integrity. In the ERC, alterations of oligodendrocyte numbers have not been investigated until now.
Microarray (Hakak et al., 2001, Aston et al., 2004, Katsel et al., 2005) and quantitative RT-PCR studies (Aberg et al., 2006, Dracheva et al., 2006) confirm the implication of oligodendrocyte and myelin in the pathogenesis of schizophrenia by revealing down-regulation of multiple oligodendrocyte and/or myelin-related genes in different brain areas in schizophrenia (Haroutunian et al., 2007). Among them, myelin basic protein (MBP) gene expression was decreased in the PFC (Tkachev et al., 2003), although this result was not replicated in other brain regions (Dracheva et al., 2006). MBP gene, which maps on 18q23, is expressed in oligodendrocytes and included in the list of candidate genes for schizophrenia (Le-Niculescu et al., 2007). Its protein product is absolutely required for the formation of intact myelin (Roach et al., 1985, Readhead et al., 1987) and comprises 30% of CNS myelin (Givogri et al., 2000). Reduced MBP immunoreactivity has been reported in the anterior frontal cortex of schizophrenia patients who died of suicide (Honer et al., 1999), as well as in the hippocampus of female schizophrenia patients (Chambers and Perrone-Bizzozero, 2004), although not all studies were able to replicate this finding (Beasley et al., 2005).
The ERC is closely connected to the hippocampal formation (perforant path), linking cortical areas to the hippocampus (Krimer et al., 1997a, Krimer et al., 1997b). MRI and post-mortem studies revealed a smaller ERC volume in schizophrenia patients (Falkai et al., 1988, Prasad et al., 2004, Kalus et al., 2005). Investigation of abnormal cytoarchitecture in limbic cortices has been most compelling with relevance to neurodevelopment (Jakob and Beckmann, 1986, Arnold et al., 1997). Additional studies revealed reduced number and smaller neuron size in layer II of the ERC in schizophrenia (Falkai et al., 1988, Arnold et al., 1995). Abnormal dispersion of neurons in layer II of the ERC (pre-alpha-cell clusters) has also been reported, suggesting migrational disturbances in schizophrenia (Jakob and Beckmann, 1986, Arnold et al., 1997, Falkai et al., 2000), although some studies could not replicate this finding (Akil and Lewis, 1997, Krimer et al., 1997a, Krimer et al., 1997b, Bernstein et al., 1998).
Recently we confirmed migrational disturbances in the ERC in schizophrenia. Pre-alpha-cell clusters were situated significantly closer to the gray–white matter junction compared to normal controls (Kovalenko et al., 2003). No increase in absolute glial cell numbers was reported in the ERC, although subdivision between the different glial cell subtypes was not performed (Falkai et al., 1988). Since impaired neuron-to-glial interactions during the migration phase could lead to abnormalities in final laminar position, we performed layer specific measurements of MBP expression in adjacent sections of the left ERC in the same set of samples used in our previous investigation (Kovalenko et al., 2003) and hypothesised that the migrational disturbances of pre-alpha-cell clusters observed in the aforementioned study relate to decreased expression of MBP in schizophrenia.
Section snippets
Results
ANOVA with factors diagnosis and gender revealed a significant reduction in mean MBP stain-intensity in schizophrenia patients (mean difference:-30%, F = 6.6, p = 0.018, Fig. 3). Separate analysis of MBP stain-intensity in layers I-VI of the ERC revealed reduced absolute MBP stain-intensity in layer III (-59%, Mann-Whitney U test: Z = -2.4, p = 0.014, Fig. 4) and layer IV (− 50%, ANOVA: F = 10.0, p = 0.004, Fig. 5) in schizophrenia patients. No significant differences in absolute MBP stain-intensity were
Discussion
According to our knowledge, this is the first study reporting reduced MBP expression in the left ERC in schizophrenia. This finding can be interpreted in two ways, both relevant for the pathophysiology of schizophrenia: on the one hand as a mark of distorted myelination, on the other hand as a sign of reduced oligodendrocyte function.
Numerous lines of inquiry implicate “miswiring” and disconnectivity among different brain regions as a central abnormality in schizophrenia (Arnold, 2000, Davis et
Cases
We studied brains from 16 patients with schizophrenia [6 males and 10 females; age 52.5 ± 12.11 years (mean ± SD)]. After retrospective review of medical charts, two psychiatrists confirmed independently the diagnosis for each case according to the DSM-IV criteria for schizophrenia. Control brains were obtained from 10 subjects without history of neuropsychiatric disorder [(4 males and 6 females; mean age 59.2 ± 13.47 years (mean ± SD)] (Table 1). All cases were examined by a neuropathologist and found
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2012, Schizophrenia ResearchCitation Excerpt :Furthermore, we recently proposed that antipsychotic medications may promote white matter development and specifically intracortical myelin (ICM) as one of their mechanisms of action (Bartzokis, 2012). Post-mortem studies of chronic SZ support the existence of an ICM deficit with cytology data revealing cortical glial deficits in SZ due primarily to lower numbers of oligodendrocytes and myelin stain data confirming an ICM deficit that seems particularly prominent in the frontal lobes (Hof et al., 2002; Flynn et al., 2003; Hof et al., 2003; Chambers and Perrone-Bizzozero, 2004; Uranova et al., 2004; Vostrikov et al., 2007; Beasley et al., 2009; Parlapani et al., 2009; Schmitt et al., 2009; Uranova et al., 2011) (reviewed in Bartzokis, 2011). Imaging studies that assessed white matter volume (Bartzokis et al., 2003; Ho et al., 2003; Whitford et al., 2007; Cocchi et al., 2009) (reviewed in Bartzokis, 2002; Bartzokis, 2011) provided consistent evidence of a deficient myelination trajectory that, unlike the rising trajectory of healthy individuals, ceases its development during early adulthood.
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2011, Psychiatry ResearchCitation Excerpt :In addition, recent studies have demonstrated that QKI is necessary and sufficient for promoting rodent oligodendrocyte differentiation (Chen et al., 2007). On the other hand, myelin basic protein (MBP), another myelination-related factor that has been reported to be differentially expressed in schizophrenia (Martins-de-Souza, 2010), is essential for myelin compaction, and is the only major myelin structural protein whose absence causes failure in central nervous system myelination (Parlapani et al., 2009). Additionally, MBP mRNA is the best-characterized QKI mRNA ligand (Larocque et al., 2002), and it binds QKI with a higher efficiency in vivo than other myelin-related mRNAs (Li et al., 2000; Zhao et al., 2006).
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Authors contributed equally.