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author:("rousso, Panos")
2.  Convergent Findings for Abnormalities of the NF-κB Signaling Pathway in Schizophrenia 
Neuropsychopharmacology  2012;38(3):533-539.
Neurons exhibit a constitutive level of nuclear factor-κB (NF-κB) signaling and this pathway plays a significant role in neurite outgrowth, activity-dependent plasticity, and cognitive function. Transcription factor analysis was performed in a microarray data set profiled in four different brain regions (n=54 comparison group; n=53 schizophrenia (SZ)). An independent postmortem cohort was used for gene expression (n=24 comparison group; n=22 SZ), protein abundance (n=8 comparison group; n=8 SZ), and NF-κB nuclear activity (n=10 comparison group; n=10 SZ) quantification. Expression quantitative trait locus analysis was performed using publicly available data. Prepulse inhibition (PPI) of the acoustic startle reflex was tested in healthy individuals (n=690). Comparison of microarray data showed that NF-κB was among the transcription factors associated with the differential expression of genes in cases vs controls. NF-κB gene and protein levels and nuclear activation were significantly decreased in the superior temporal gyrus of patients with SZ. Upstream NF-κB genes related to translocation were significantly dysregulated in SZ. The gene expression levels of an NF-κB-associated importin (KPNA4: one of the proteins responsible for the translocation of NF-κB to the nucleus) was decreased in SZ and an SNP within the KPNA4 locus was associated with susceptibility to SZ, reduced KPNA4 expression levels and attenuated PPI of the startle reflex in healthy control subjects. These findings implicate abnormalities of the NF-κB signaling pathway in SZ and provide evidence for an additional possible mechanism affecting the translocation of NF-κB signaling to the nucleus.
doi:10.1038/npp.2012.215
PMCID: PMC3547205  PMID: 23132271
biological psychiatry; gene expression; human postmortem; neurogenetics; neurophysiology; prepulse inhibition; schizophrenia / antipsychotics; transcription factor; postmortem; mRNA; superior temporal gyrus; prepulse inhibition; importin; transcription factor
3.  Schizophrenia: susceptibility genes and oligodendroglial and myelin related abnormalities 
Given that the genetic risk for schizophrenia is highly polygenic and the effect sizes, even for rare or de novo events, are modest at best, it has been suggested that multiple biological pathways are likely to be involved in the etiopathogenesis of the disease. Most efforts in understanding the cellular basis of schizophrenia have followed a “neuron-centric” approach, focusing on alterations in neurotransmitter systems and synapse cytoarchitecture. However, multiple lines of evidence coming from genetics and systems biology approaches suggest that apart from neurons, oligodendrocytes and potentially other glia are affected from schizophrenia risk loci. Neurobiological abnormalities linked with genetic association signal could identify abnormalities that are more likely to be primary, versus environmentally induced changes or downstream events. Here, we summarize genetic data that support the involvement of oligodendrocytes in schizophrenia, providing additional evidence for a causal role with the disease. Given the undeniable evidence of both neuronal and glial abnormalities in schizophrenia, we propose a neuro-glial model that invokes abnormalities at the node of Ranvier as a functional unit in the etiopathogenesis of the disease.
doi:10.3389/fncel.2014.00005
PMCID: PMC3896818  PMID: 24478629
systems biology; polygenic; node of Ranvier; disconnectivity; GWAS
4.  Anterior limb of the internal capsule in schizotypal personality disorder: Fiber-tract counting, volume, and anisotropy 
Schizophrenia research  2012;141(0):119-127.
Mounting evidence suggests that white matter abnormalities and altered subcortical–cortical connectivity may be central to the pathology of schizophrenia (SZ). The anterior limb of the internal capsule (ALIC) is an important thalamo-frontal white-matter tract shown to have volume reductions in SZ and to a lesser degree in schizotypal personality disorder (SPD). While fractional anisotropy (FA) and connectivity abnormalities in the ALIC have been reported in SZ, they have not been examined in SPD. In the current study, magnetic resonance (MRI) and diffusion tensor imaging (DTI) were obtained in age- and sex-matched individuals with SPD (n=33) and healthy controls (HCs; n=38). The ALIC was traced bilaterally on five equally spaced dorsal-to-ventral axial slices from each participant’s MRI scan and co-registered to DTI for the calculation of FA. Tractography was used to examine tracts between the ALIC and two key Brodmann areas (BAs; BA10, BA45) within the dorsolateral prefrontal cortex (DLPFC). Compared with HCs, the SPD participants exhibited (a) smaller relative volume at the mid-ventral ALIC slice level but not the other levels; (b) normal FA within the ALIC; (c) fewer relative number of tracts between the most-dorsal ALIC levels and BA10 but not BA45 and (d) fewer dorsal ALIC–DLPFC tracts were associated with greater symptom severity in SPD. In contrast to prior SZ studies that report lower FA, individuals with SPD show sparing. Our findings are consistent with a pattern of milder thalamo-frontal dysconnectivity in SPD than schizophrenia.
doi:10.1016/j.schres.2012.08.022
PMCID: PMC3742803  PMID: 22995934
Schizotypal personality disorder; Diffusion tensor imaging; Tractography; Magnetic resonance imaging; Anisotropy; Internal capsule
5.  Differences in DNA methylation between human neuronal and glial cells are concentrated in enhancers and non-CpG sites 
Nucleic Acids Research  2013;42(1):109-127.
We applied Illumina Human Methylation450K array to perform a genomic-scale single-site resolution DNA methylation analysis in neuronal and nonneuronal (primarily glial) nuclei separated from the orbitofrontal cortex of postmortem human brain. The findings were validated using enhanced reduced representation bisulfite sequencing. We identified thousands of sites differentially methylated (DM) between neuronal and nonneuronal cells. The DM sites were depleted within CpG-island–containing promoters but enriched in predicted enhancers. Classification of the DM sites into those undermethylated in neurons (neuronal type) and those undermethylated in nonneuronal cells (glial type), combined with findings of others that methylation within control elements typically negatively correlates with gene expression, yielded large sets of predicted neuron-specific and non–neuron-specific genes. These sets of predicted genes were in excellent agreement with the available direct measurements of gene expression in human and mouse. We also found a distinct set of DNA methylation patterns that were unique for neuronal cells. In particular, neuronal-type differential methylation was overrepresented in CpG island shores, enriched within gene bodies but not in intergenic regions, and preferentially harbored binding motifs for a distinct set of transcription factors, including neuron-specific activity-dependent factors. Finally, non-CpG methylation was substantially more prevalent in neurons than in nonneuronal cells.
doi:10.1093/nar/gkt838
PMCID: PMC3874157  PMID: 24057217
7.  The Association of Schizophrenia Risk -Amino Acid Oxidase Polymorphisms With Sensorimotor Gating, Working Memory and Personality in Healthy Males 
Neuropsychopharmacology  2011;36(8):1677-1688.
There is evidence supporting a role for the -amino acid oxidase (DAO) locus in schizophrenia. This study aimed to determine the relationship of five single-nucleotide polymorphisms (SNPs) within the DAO gene identified as promising schizophrenia risk genes (rs4623951, rs2111902, rs3918346, rs3741775, and rs3825251) to acoustic startle, prepulse inhibition (PPI), working memory, and personality dimensions. A highly homogeneous study entry cohort (n=530) of healthy, young male army conscripts (n=703) originating from the Greek LOGOS project (Learning On Genetics Of Schizophrenia Spectrum) underwent PPI of the acoustic startle reflex, working memory, and personality assessment. The QTPHASE from the UNPHASED package was used for the association analysis of each SNP or haplotype data, with p-values corrected for multiple testing by running 10 000 permutations of the data. The rs4623951_T-rs3741775_G and rs4623951_T-rs2111902_T diplotypes were associated with reduced PPI and worse performance in working memory tasks and a personality pattern characterized by attenuated anxiety. Median stratification analysis of the risk diplotype group (ie, those individuals homozygous for the T and G alleles (TG+)) showed reduced PPI and working memory performance only in TG+ individuals with high trait anxiety. The rs4623951_T allele, which is the DAO polymorphism most strongly associated with schizophrenia, might tag a haplotype that affects PPI, cognition, and personality traits in general population. Our findings suggest an influence of the gene in the neural substrate mediating sensorimotor gating and working memory, especially when combined with high anxiety and further validate DAO as a candidate gene for schizophrenia and spectrum disorders.
doi:10.1038/npp.2011.49
PMCID: PMC3138651  PMID: 21471957
prepulse inhibition; working memory; personality; -amino acid oxidase; schizophrenia; Glutamate; Psychiatry & Behavioral Sciences; Cognition; Neurogenetics; Sensorimotor Gating
8.  Cannabis-Dependence Risk Relates to Synergism between Neuroticism and Proenkephalin SNPs Associated with Amygdala Gene Expression: Case-Control Study 
PLoS ONE  2012;7(6):e39243.
Background
Many young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown.
Methodology/Principal Findings
Healthy young adults (18–27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%–19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect.
Conclusions/Significance
Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk.
doi:10.1371/journal.pone.0039243
PMCID: PMC3382183  PMID: 22745721
9.  Astrocyte and Glutamate Markers in the Superficial, Deep, and White Matter Layers of the Anterior Cingulate Gyrus in Schizophrenia 
Neuropsychopharmacology  2011;36(6):1171-1177.
Most studies of the neurobiology of schizophrenia have focused on neurotransmitter systems, their receptors, and downstream effectors. Recent evidence suggests that it is no longer tenable to consider neurons and their functions independently of the glia that interact with them. Although astrocytes have been viewed as harbingers of neuronal injury and CNS stress, their principal functions include maintenance of glutamate homeostasis and recycling, mediation of saltatory conduction, and even direct neurotransmission. Results of studies of astrocytes in schizophrenia have been variable, in part because of the assessment of single and not necessarily universal markers and/or assessment of non-discrete brain regions. We used laser capture microdissection to study three distinct partitions of the anterior cingulate gyrus (layers I–III, IV–VI, and the underlying white matter) in the brains of 18 well-characterized persons with schizophrenia and 21 unaffected comparison controls. We studied the mRNA expression of nine specific markers known to be localized to astrocytes. The expression of astrocyte markers was not altered in the superficial layers or the underlying white matter of the cingulate cortex of persons with schizophrenia. However, the expression of some astrocyte markers (diodinase type II, aquaporin-4, S100β, glutaminase, excitatory amino-acid transporter 2, and thrombospondin), but not of others (aldehyde dehydrogenase 1 family member L1, glial fibrillary acidic protein, and vimentin) was significantly reduced in the deep layers of the anterior cingulate gyrus. These findings suggest that a subset of astrocytes localized to specific cortical layers is adversely affected in schizophrenia and raise the possibility of glutamatergic dyshomeostasis in selected neuronal populations.
doi:10.1038/npp.2010.252
PMCID: PMC3077461  PMID: 21270770
astrocytes; cortical layers; postmortem; mRNA; schizophrenia; molecular & cellular neurobiology; biological psychiatry; neuroanatomy; neurotransmitters; glia; postmortem; astrocyte; schizophrenia; cingulate
10.  Astrocyte and glutamate markers in the superficial, deep and white matter layers of the anterior cingulate gyrus in schizophrenia 
Most studies of the neurobiology of schizophrenia have focused on neurotransmitter systems, their receptors and downstream effectors. Recent evidence suggests that it is no longer tenable to consider neurons and their functions independently of the glia that interact with them. Although astrocytes have been viewed as harbingers of neuronal injury and CNS stress, their principal functions include maintenance glutamate homeostasis and recycling, mediation of saltatory conduction and even direct neurotransmission. Results of studies of astrocytes in schizophrenia have been variable, in part due to the assessment of single and not necessarily universal markers and/or assessment of non-discrete brain regions. We used laser capture microdissection to study 3 distinct partitions of the anterior cingulate gyrus (layers I–III, IV–VI, underlying white matter) in the brains of 18 well-characterized persons with schizophrenia and 21 unaffected comparison controls. We studied the mRNA expression of 9 specific markers known to be localized to astrocytes. The expression of astrocyte markers was not altered in the superficial layers or the underlying white matter of the cingulate cortex of persons with schizophrenia. However the expression of some astrocyte markers (diodinase type II, aquaporin-4, S100β, glutaminase, excitatory amino acid transporter 2 and thrombospondin), but not to others (aldehyde dehydrogenase 1 family member L1, glial fibrillary acidic protein and vimentin) was significantly reduced in the deep layers of the anterior cingulate gyrus. These findings suggest that a subset of astrocytes localized to specific cortical layers are adversely affected in schizophrenia and raise the possibility of glutamatergic dyshomeostasis in selected neuronal populations.
doi:10.1038/npp.2010.252
PMCID: PMC3077461  PMID: 21270770
Astrocytes; cortical layers; postmortem; mRNA; schizophrenia

Results 1-10 (10)