scholarly journals Reduced Insulin-Like Growth Factor Family Member Expression Predicts Neurogenesis Marker Expression in the Subependymal Zone in Schizophrenia and Bipolar Disorder

2020 ◽  
Author(s):  
Christin Weissleder ◽  
Maree J Webster ◽  
Guy Barry ◽  
Cynthia Shannon Weickert
Keyword(s):  
Bipolar Disorder ◽  
Growth Factor ◽  
Psychiatric Disorders ◽  
Family Member ◽  
Inhibitory Interneuron ◽  
Trophic Factors ◽  
Trophic Factor ◽  
Insulin Like Growth Factor ◽  
Neuronal Progenitor ◽  
Subependymal Zone

Abstract The generation of inhibitory interneurons from neural stem cells in the subependymal zone is regulated by trophic factors. Reduced levels of trophic factors are associated with inhibitory interneuron dysfunction in the prefrontal cortex and hippocampus in psychiatric disorders, yet the extent to which altered trophic support may underpin deficits in inhibitory interneuron generation in the neurogenic niche remains unexplored in schizophrenia and bipolar disorder. We determined whether the expression of ligands, bioavailability-regulating binding proteins, and cognate receptors of 4 major trophic factor families (insulin-like growth factor [IGF], epidermal growth factor [EGF], fibroblast growth factor [FGF], and brain-derived neurotrophic factor [BDNF]) are changed in schizophrenia and bipolar disorder compared to controls. We used robust linear regression analyses to determine whether altered expression of trophic factor family members predicts neurogenesis marker expression across diagnostic groups. We found that IGF1 mRNA was decreased in schizophrenia and bipolar disorder compared with controls (P ≤ .006), whereas both IGF1 receptor (IGF1R) and IGF binding protein 2 (IGFBP2) mRNAs were reduced in schizophrenia compared with controls (P ≤ .02). EGF, FGF, and BDNF family member expression were all unchanged in both psychiatric disorders compared with controls. IGF1 expression positively predicted neuronal progenitor and immature neuron marker mRNAs (P ≤ .01). IGFBP2 expression positively predicted neural stem cell and neuronal progenitor marker mRNAs (P ≤ .001). These findings provide the first molecular evidence of decreased IGF1, IGF1R, and IGFBP2 mRNA expression in the subependymal zone in psychiatric disorders, which may potentially impact neurogenesis in schizophrenia and bipolar disorder.

scholarly journals M174. REDUCED CHEMOKINE SIGNALLING CAPACITY IS ASSOCIATED WITH INHIBITORY INTERNEURON DYSFUNCTION IN SUBCORTICAL BRAIN REGIONS IN SCHIZOPHRENIA AND BIPOLAR DISORDER

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S202-S203
Author(s):  
Christin Weissleder ◽  
Maree J Webster ◽  
Cynthia Shannon Weickert
Keyword(s):  
Bipolar Disorder ◽  
Caudate Nucleus ◽  
Psychiatric Disorders ◽  
Family Member ◽  
Inhibitory Interneuron ◽  
Inhibitory Interneurons ◽  
Stem Cell Maintenance ◽  
Neuronal Progenitors ◽  
Cxc Chemokine ◽  
Chemokine Family

Abstract Background The subependymal zone (SEZ) adjacent to the lateral ventricles represents the largest reservoir of postnatally-generated cortical and striatal inhibitory interneurons in the human brain. Expression of markers representing the generation of neuronal progenitors from neural stem cells is reduced in the adult SEZ in schizophrenia and bipolar disorder; however, underlying mechanisms and relationships to inhibitory interneuron dysfunction remain unknown. Stem cell maintenance, neuronal migration and cell survival are regulated by signaling of the CXC motif chemokine 12 (CXCL12) through CXC motif chemokine receptors 4 (CXCR4) and 7 (CXCR7), which are increasingly implicated in the pathophysiology of psychiatric disorders. Methods Post-mortem tissue was obtained from 33 schizophrenia, 32 bipolar disorder and 33 control cases from the Stanley Medical Research Institute. SEZ and caudate nucleus tissue was dissected from 60 µm sections for RNA isolation and cDNA synthesis. Gene expression of CXCL12, CXCR4 and CXCR7 were determined by quantitative polymerase chain reactions. Semi-partial correlations were performed to assess whether CXC chemokine family member mRNAs may correlate with markers of neural stem cells (PROM1, GFAPD), neuronal progenitors (SOX2, ASCL1) and inhibitory interneurons (CALB2, NPY) in the SEZ and caudate nucleus. Results In the SEZ, CXCL12 mRNA was decreased in schizophrenia compared to controls and bipolar disorder (14–24%, all p≤0.03). CXCR4 and CXCR7 mRNAs were both decreased in schizophrenia and bipolar disorder compared to controls (9–33%, all p≤0.05). CXCL12, CXCR4 and CXCR7 expression positively correlated with PROM1, GFAPD, SOX2 and ASCL1 mRNAs (0.28≥sr≤0.61). In the caudate nucleus, CXCL12 mRNA was decreased in schizophrenia and bipolar disorder compared to controls (19–26%, all p≤0.05). CXCR4 mRNA was decreased in schizophrenia compared to controls (20%, p=0.01), while CXCR7 expression did not significantly differ across diagnostic groups. CALB2 and NPY mRNAs were increased in bipolar disorder compared to controls (13–27%, all p≤0.05). CXCR4 expression positively correlated with CALB2 mRNA (sr=0.26), while CXCR7 expression negatively correlated with NPY mRNA (sr=0.26). Discussion These findings provide the first molecular evidence of decreased CXC chemokine family member expression in the SEZ and caudate nucleus in psychiatric disorders, with exacerbated deficits in schizophrenia compared to bipolar disorder. Dysregulated CXC chemokine family member expression may hamper neural stem cell maintenance and neuronal differentiation, which may contribute to inhibitory interneuron dysfunction in psychiatric disorders. Future work will determine the cellular localisation of CXCR4 and CXCR7 expression in the SEZ and caudate nucleus to disentangle the regulatory role of CXCL12 signalling in the generation, migration and survival of inhibitory interneurons in the human brain.

scholarly journals O11.5. INCREASED INFLAMMATION AND MACROPHAGE INFILTRATION IS ASSOCIATED WITH ALTERED SUBEPENDYMAL ZONE NEUROGENESIS IN SCHIZOPHRENIA BUT NOT BIPOLAR DISORDER

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S28-S29
Author(s):  
Hayley North ◽  
Christin Weissleder ◽  
Maina Bitar ◽  
Janice M Fullerton ◽  
Rachel Sager ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bipolar Disorder ◽  
Cluster Analysis ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
Differentially Expressed Gene ◽  
Inhibitory Interneuron ◽  
Stem Cell Marker ◽  
Neuronal Progenitor ◽  
Subependymal Zone

Abstract Background Inflammation is implicated in the pathogenesis of schizophrenia and bipolar disorder. Inflammation regulates neurogenesis, and markers for stem cells and neuronal progenitors are reduced in schizophrenia and bipolar disorder in the subependymal zone (SEZ) – the brain’s largest region of neurogenesis. This research aimed to discover core differences in gene expression and cellular composition in the SEZ in psychiatric disorders that may contribute to dysregulated neurogenesis. Methods We performed total RNA sequencing in the SEZ of 20 post-mortem schizophrenia and 21 control brains. Quantitative PCR (qPCR) and immunohistochemistry were performed in 32 schizophrenia and 32 control overlapping cases and 29 bipolar disorder cases. Immunohistochemistry was used for quantification and localisation of CD163+ macrophages. Cluster-analysis of IL6, IL6R, IL1R1 and SERPINA3 expression defined low and high inflammation subgroups, which were used to compare neurogenesis marker expression. Results Out of >60,000 genes, the most significantly differentially expressed gene in schizophrenia was CD163, a macrophage marker, which was increased 3.3 times compared to controls and confirmed by qPCR. Abundant CD163+ macrophages were located surrounding blood vessels, in the parenchyma and seem to infiltrate throughout the SEZ where neural stem and progenitor cells typically reside. Macrophage cell density was increased in schizophrenia compared to controls and bipolar disorder (by 29% and 61%; p = 0.017 and p = 0.002 respectively). CD163 expression positively correlated with the quiescent neural stem cell marker GFAPδ (r = 0.56, p = 0.001), and negatively correlated with neuronal progenitor marker ASCL1 (r = - 0.40, p = 0.032) in schizophrenia but not bipolar disorder. Cluster analysis of inflammatory gene expression revealed 40% of schizophrenia but only 10% of control cases were highly inflamed. The high inflammation schizophrenia subgroup had increased CD163 and GFAPδ expression but decreased ASCL1 expression (all p < 0.026). Discussion Increased macrophages in the SEZ is a key difference in schizophrenia pathology and potentially drives heightened inflammation in a subgroup. Inflammation has varied effects on different stages of neurogenesis in schizophrenia but not bipolar disorder, implicating divergent mechanisms leading to reduced neurogenesis in each psychiatric condition. In schizophrenia, macrophages and high inflammation seem to reduce neuronal differentiation and sustain neural stem cell quiescence, likely blunting stem cell proliferation. Therefore, reduced SEZ neurogenesis across the lifespan in schizophrenia may contribute to the widely reported inhibitory interneuron deficits.

scholarly journals A schizophrenia subgroup with elevated inflammation displays reduced microglia, increased peripheral immune cell and altered neurogenesis marker gene expression in the subependymal zone

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hayley F. North ◽  
Christin Weissleder ◽  
Janice M. Fullerton ◽  
Rachel Sager ◽  
Maree J. Webster ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bipolar Disorder ◽  
Psychiatric Disorders ◽  
Immune Cells ◽  
Immune Cell ◽  
Marker Gene ◽  
Stem Cell Marker ◽  
Neuronal Progenitor ◽  
Immature Neuron ◽  
Subependymal Zone

AbstractInflammation regulates neurogenesis, and the brains of patients with schizophrenia and bipolar disorder have reduced expression of neurogenesis markers in the subependymal zone (SEZ), the birthplace of inhibitory interneurons. Inflammation is associated with cortical interneuron deficits, but the relationship between inflammation and reduced neurogenesis in schizophrenia and bipolar disorder remains unexplored. Therefore, we investigated inflammation in the SEZ by defining those with low and high levels of inflammation using cluster analysis of IL6, IL6R, IL1R1 and SERPINA3 gene expression in 32 controls, 32 schizophrenia and 29 bipolar disorder cases. We then determined whether mRNAs for markers of glia, immune cells and neurogenesis varied with inflammation. A significantly greater proportion of schizophrenia (37%) and bipolar disorder cases (32%) were in high inflammation subgroups compared to controls (10%, p < 0.05). Across the high inflammation subgroups of psychiatric disorders, mRNAs of markers for phagocytic microglia were reduced (P2RY12, P2RY13), while mRNAs of markers for perivascular macrophages (CD163), pro-inflammatory macrophages (CD64), monocytes (CD14), natural killer cells (FCGR3A) and adhesion molecules (ICAM1) were increased. Specific to high inflammation schizophrenia, quiescent stem cell marker mRNA (GFAPD) was reduced, whereas neuronal progenitor (ASCL1) and immature neuron marker mRNAs (DCX) were decreased compared to low inflammation control and schizophrenia subgroups. Thus, a heightened state of inflammation may dampen microglial response and recruit peripheral immune cells in psychiatric disorders. The findings elucidate differential neurogenic responses to inflammation within psychiatric disorders and highlight that inflammation may impair neuronal differentiation in the SEZ in schizophrenia.

Peripheral insulin-like growth factor and glutamate-related antibodies in bipolar disorder and lithium prophylaxis

2019 ◽  
Vol 29 ◽  
pp. S40
Author(s):  
E. Ferensztajn ◽  
M. Kaczmarek ◽  
M. Wójcicka ◽  
E. Kaufman-Szukalska ◽  
S. Dziuda ◽  
...  
Keyword(s):  
Bipolar Disorder ◽  
Growth Factor ◽  
Insulin Like Growth Factor

scholarly journals Defining human insulin-like growth factor I gene regulation

2016 ◽  
Vol 311 (2) ◽  
pp. E519-E529 ◽  
Author(s):  
Aditi Mukherjee ◽  
Damir Alzhanov ◽  
Peter Rotwein
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Biological Effects ◽  
Model Systems ◽  
Trophic Factors ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I ◽  
I Gene

Growth hormone (GH) plays an essential role in controlling somatic growth and in regulating multiple physiological processes in humans and other species. Insulin-like growth factor I (IGF-I), a conserved, secreted 70-amino acid peptide, is a critical mediator of many of the biological effects of GH. Previous studies have demonstrated that GH rapidly and potently promotes IGF-I gene expression in rodents and in some other mammals through the transcription factor STAT5b, leading to accumulation of IGF-I mRNAs and production of IGF-I. Despite this progress, very little is known about how GH or other trophic factors control human IGF1 gene expression, in large part because of the absence of any cellular model systems that robustly express IGF-I. Here, we have addressed mechanisms of regulation of human IGF-I by GH after generating cells in which the IGF1 chromosomal locus has been incorporated into a mouse cell line. Using this model, we found that physiological levels of GH rapidly stimulate human IGF1 gene transcription and identify several potential transcriptional enhancers in chromatin that bind STAT5b in a GH-regulated way. Each of the putative enhancers also activates a human IGF1 gene promoter in reconstitution experiments in the presence of the GH receptor, STAT5b, and GH. Thus we have developed a novel experimental platform that now may be used to determine how human IGF1 gene expression is controlled under different physiological and pathological conditions.

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