| 1 | Biol. Psychiatry 2008 Nov 64: 901-3 |
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| PMID | 18707678 |
| Title | Influence of vascular endothelial growth factor variation on human hippocampus morphology. |
| Abstract | Morphological abnormalities in hippocampus have been implicated in neuropsychiatric disorders, including depression, schizophrenia, and dementia. Vascular endothelial growth factor (VEGF) has been demonstrated to have neurogenic effects in the hippocampus in rats. However, influence of VEGF variation on hippocampus morphology in humans has yet to be shown. Here, an integrated genetic and neuroimaging approach was used to investigate whether VEGF variation influences hippocampus morphology in humans. High-resolution magnetic resonance imaging and voxel-based morphometry were used to identify the influence of genetic variation of VEGFA [rs833068 (SNP-1), rs833070 (SNP-2), rs2146323 (SNP-3) and rs3025020 (SNP-4)] on brain morphology in 47 healthy individuals. Variation in VEGFA SNP-2 and SNP-3 showed significant effects on hippocampus concentration. The findings suggest that effects of VEGF in hippocampus found in rats extend to humans; further understanding of effects of VEGFA variation might have important implications in identifying individuals more vulnerable to hippocampus pathology as well as those neuropsychiatric populations most likely to benefit from VEGF-mediated interventions. |
| SCZ Keywords | schizophrenia |
| 2 | Mol Autism 2014 -1 5: 38 |
| PMID | 25061506 |
| Title | Integrative proteomic analysis of the NMDA NR1 knockdown mouse model reveals effects on central and peripheral pathways associated with schizophrenia and autism spectrum disorders. |
| Abstract | Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1(neo-/-)) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symptoms in the continuum of other psychiatric diseases, particularly autism spectrum disorders (ASD). As previous studies have mostly focussed on behavioural readouts, a molecular characterisation of this model will help to identify novel biomarkers or potential drug targets. Here, we have used multiplex immunoassay analyses to investigate peripheral analyte alterations in serum of NR1(neo-/-) mice, as well as a combination of shotgun label-free liquid chromatography mass spectrometry, bioinformatic pathway analyses, and a shotgun-based 40-plex selected reaction monitoring (SRM) assay to investigate altered molecular pathways in the frontal cortex and hippocampus. All findings were cross compared to identify translatable findings between the brain and periphery. Multiplex immunoassay profiling led to identification of 29 analytes that were significantly altered in sera of NR1(neo-/-) mice. The highest magnitude changes were found for neurotrophic factors (VEGFA, EGF, IGF-1), apolipoprotein A1, and fibrinogen. We also found decreased levels of several chemokines. Following this, LC-MS(E) profiling led to identification of 48 significantly changed proteins in the frontal cortex and 41 in the hippocampus. In particular, MARCS, the mitochondrial pyruvate kinase, and CamKII-alpha were affected. Based on the combination of protein set enrichment and bioinformatic pathway analysis, we designed orthogonal SRM-assays which validated the abnormalities of proteins involved in synaptic long-term potentiation, myelination, and the ERK-signalling pathway in both brain regions. In contrast, increased levels of proteins involved in neurotransmitter metabolism and release were found only in the frontal cortex and abnormalities of proteins involved in the purinergic system were found exclusively in the hippocampus. Taken together, this multi-platform profiling study has identified peripheral changes which are potentially linked to central alterations in synaptic plasticity and neuronal function associated with NMDAR-NR1 hypofunction. Therefore, the reported proteomic changes may be useful as translational biomarkers in human and rodent model drug discovery efforts. |
| SCZ Keywords | schizophrenia |
| 3 | Transl Psychiatry 2014 -1 4: e363 |
| PMID | 24548878 |
| Title | Long-term effects of maternal immune activation on depression-like behavior in the mouse. |
| Abstract | Depression is a debilitating mental disease affecting a large population worldwide, the pathophysiological mechanisms of which remain incompletely understood. Prenatal infection and associated activation of the maternal immune system (MIA) are prominently related to an increased risk for the development of several psychiatric disorders including schizophrenia and autism in the offsprings. However, the role of MIA in the etiology of depression and its neurobiological basis are insufficiently investigated. Here we induced MIA in mice by challenge with polyinosinic:polycytidylic phosphate salt-a synthetic analog of double-stranded RNA, which enhances maternal levels of the cytokine interleukin-6 (IL-6)-and demonstrate a depression-like behavioral phenotype in adult offsprings. Adult offsprings additionally show deficits in cognition and hippocampal long-term potentiation (LTP) accompanied by disturbed proliferation of newborn cells in the dentate gyrus and compromised neuronal maturation and survival. The behavioral, neurogenic and functional deficiencies observed are associated with reduced hippocampal expression of vascular endothelial growth factor (VEGF)A-VEGFR2. IL-6-STAT3-dependent aberrant VEGFA-VEGFR2 signaling is proposed as neurobiological mechanism mediating the effects of MIA on the developing fetal brain and ensuing consequences in adulthood. |
| SCZ Keywords | schizophrenia |
| 4 | Adv Gerontol 2015 -1 28: 228-47 |
| PMID | 26856084 |
| Title | GENETICS OF HUMAN AGE RELATED DISORDERS. |
| Abstract | Aging is an inevitable biological phenomenon. The incidence of age related disorders (ARDs) such as cardiovascular diseases, cancer, arthritis, dementia, osteoporosis, diabetes, neurodegenerative diseases increase rapidly with aging. ARDs are becoming a key social and economic trouble for the world's elderly population (above 60 years), which is expected to reach 2 billion by 2050. Advancement in understanding of genetic associations, particularly through genome wide association studies (GWAS), has revealed a substantial contribution of genes to human aging and ARDs. In this review, we have focused on the recent understanding of the extent to which genetic predisposition may influence the aging process. Further analysis of the genetic association studies through pathway analysis several genes associated with multiple ARDs have been highlighted such as apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), cadherin 13 (CDH13), CDK5 regulatory subunit associated protein 1 (CDKAL-1), methylenetetrahydrofolate reductase (MTHFR), disrupted in schizophrenia 1 (DISC1), nitric oxide synthase 3 (NOS3), paraoxonase 1 (PON1), indicating that these genes could play a pivotal role in ARD causation. These genes were found to be significantly enriched in Jak-STAT signalling pathway, asthma and allograft rejection. Further, interleukin-6 (IL-6), insulin (INS), vascular endothelial growth factor A (VEGFA), estrogen receptor1 (ESR1), transforming growth factor, beta 1(TGFB1) and calmodulin 1 (CALM1) were found to be highly interconnected in network analysis. We believe that extensive research on the presence of common genetic variants among various ARDs may facilitate scientists to understand the biology behind ARDs causation. |
| SCZ Keywords | schizophrenia |
| 5 | Neurosci. Lett. 2015 Mar 590: 121-5 |
| PMID | 25641131 |
| Title | Association study of VEGFA polymorphisms with schizophrenia in Han Chinese population. |
| Abstract | Vascular endothelial growth factor A (VEGFA) has been implicated in neurotrophy and neurogenesis, which play a pivotal role in brain development and may be involved in the pathophysiology of schizophrenia (SCZ). We hypothesized that common genetic variants in the VEGFA gene may be associated with SCZ. In our study, seven tag single nucleotide polymorphisms (SNPs) within VEGFA were genotyped in 1034 SCZ patients and 952 healthy controls in the Han Chinese population. No significant differences of allele and genotype distributions of the 7 tag SNPs were identified between SCZ patients and healthy controls. The AA genotype of rs699947 nominally decreased the risk of SCZ in recessive inheritance model (p=0.03, OR=0.65, 95%CI=0.44-0.95, adjusted p=0.18). No significant associations were found between different haplotypes and the risk of SCZ (p>0.05). Our findings suggested that the selected tag SNPs of VEGFA may not confer a susceptibility of SCZ in the Han Chinese population. |
| SCZ Keywords | schizophrenia |