Molecular control of neurogenesis in the human subependymal zone in development, aging and psychiatric disorders

The subependymal zone (SEZ) is the largest reservoir of newly-born neuronal and glial cells in the postnatal mammalian brain. These progenitor cells migrate to cortical and subcortical regions during learning or attempts at brain repair. Genetic variations and environmental risk factors associated with the development of psychiatric disorders may converge to alter subependymal neurogenesis, which may impact neuropathology or pathophysiology of schizophrenia and bipolar disorder. However, the extent of neurogenesis in the human SEZ after infancy is controversial with limited molecular exploration of the niche microenvironment. This thesis analysed expression of markers representing different cellular developmental stages of neurogenesis in relation to both glial cell markers and trophic support across the human lifespan (n = 89, 0.1-103 years), and in schizophrenia and bipolar disorder (n = 29-32 per group). I first demonstrated that markers of neural stem cells, transit amplifying progenitors and immature neurons are detectable in the SEZ across life, indicating neurogenesis persists into advanced age. I detected reduced cell proliferation and immature neuron marker expression in the aged SEZ despite stable neural stem cell and neuronal progenitor marker expression, suggesting age impacts different stages of neurogenesis. Aging was associated with alterations in the niche microenvironment, including increased microglia marker expression and reduced insulin like growth factor 1 (IGF1) expression, which may collectively impair neurogenesis in the aged SEZ. I further identified decreased expression of neural stem cell and neuronal progenitor markers in schizophrenia and bipolar disorder compared to controls, indicating that reduced neurogenic capacity is shared across these psychiatric disorders. Cell proliferation and microglia marker expression were only decreased in bipolar disorder, pointing to disease-specific alterations in the SEZ. I detected reduced IGF1 expression in both psychiatric disorders, which was positively associated with neuronal progenitor marker expression. The findings from this thesis provided the first molecular evidence of dysregulated neurogenesis alongside alterations to niche microenvironments during aging and in psychiatric disorders. Reduced IGF1 expression under physiological and pathological conditions highlights the relevance of IGF1 signalling as a potential convergence point for ensuring life-long neurogenesis in the human brain, and may represent a common therapeutic target for regenerative therapies

RNA-sequencing suggests extracellular matrix and vasculature dysregulation could impair neurogenesis in schizophrenia cases with elevated inflammation

International audienceA subgroup of schizophrenia cases with elevated inflammation have reduced neurogenesis markers and increased macrophage density in the human subependymal zone (SEZ; also termed subventricular zone or SVZ) neurogenic niche. Inflammation can impair neurogenesis; however, it is unclear which other pathways are associated with reduced neurogenesis. This research aimed to discover transcriptomic differences between inflammatory subgroups of schizophrenia in the SEZ. Total RNA sequencing was performed on SEZ tissue from schizophrenia cases, designated into low inflammation ( n = 13) and high inflammation ( n = 14) subgroups, based on cluster analysis of inflammation marker gene expression. 718 genes were differentially expressed in high compared to low inflammation schizophrenia (FDR p < 0.05) and were most significantly over-represented in the pathway ‘Hepatic Fibrosis/Hepatic Stellate-Cell Activation’. Genes in this pathway relate to extracellular matrix stability (including ten collagens) and vascular remodelling suggesting increased angiogenesis. Collagen-IV, a key element of the basement membrane and fractones, had elevated gene expression. Immunohistochemistry revealed novel collagen-IV+ fractone bulbs within the human SEZ hypocellular gap. Considering the extracellular matrix’s regulatory role in SEZ neurogenesis, fibrosis-related alterations in high inflammation schizophrenia may disrupt neurogenesis. Increased angiogenesis could facilitate immune cell transmigration, potentially explaining elevated macrophages in high inflammation schizophrenia. This discovery-driven analysis sheds light on how inflammation may contribute to schizophrenia neuropathology in the neurogenic niche

Sex- and suicide-specific alterations in the kynurenine pathway in the anterior cingulate cortex in major depression

Major depressive disorder (MDD) is a serious psychiatric disorder that in extreme cases can lead to suicide. Evidence suggests that alterations in the kynurenine pathway (KP) contribute to the pathology of MDD. Activation of the KP leads to the formation of neuroactive metabolites, including kynurenic acid (KYNA) and quinolinic acid (QUIN). To test for changes in the KP, postmortem anterior cingulate cortex (ACC) was obtained from the National Institute of Health NeuroBioBank. Gene expression of KP enzymes and relevant neuroinflammatory markers were investigated via RT-qPCR (Fluidigm) and KP metabolites were measured using liquid chromatography-mass spectrometry in tissue from individuals with MDD (n = 44) and matched nonpsychiatric controls (n = 36). We report increased IL6 and IL1B mRNA in MDD. Subgroup analysis found that female MDD subjects had significantly decreased KYNA and a trend decrease in the KYNA/QUIN ratio compared to female controls. In addition, MDD subjects that died by suicide had significantly decreased KYNA in comparison to controls and MDD subjects that did not die by suicide, while subjects that did not die by suicide had increased KYAT2 mRNA, which we hypothesise may protect against a decrease in KYNA. Overall, we found sex- and suicide-specific alterations in the KP in the ACC in MDD. This is the first molecular evidence in the brain of subgroup specific changes in the KP in MDD, which not only suggests that treatments aimed at upregulation of the KYNA arm in the brain may be favourable for female MDD sufferers but also might assist managing suicidal behaviour

Dataset for: Early life decline in neurogenesis markers and age-related changes of TrkB splice variant expression in the human subependymal zone

Neurogenesis in the subependymal zone (SEZ) declines across the human lifespan and reduced local neurotrophic support is speculated to be a contributing factor. While tyrosine receptor kinase B (TrkB) signalling is critical for neuronal differentiation, maturation and survival, little is known about subependymal TrkB expression changes during postnatal human life. In this study, we used quantitative PCR and in situ hybridisation to determine expression of the cell proliferation marker Ki67, the immature neuron marker doublecortin (DCX) and both full-length (TrkB-TK+) and truncated TrkB receptors (TrkB-TK-) in the human SEZ from infancy to middle age (n=26-35, 41 days–43 years). We further measured TrkB-TK+ and TrkB-TK- mRNAs in the SEZ from young adulthood into aging (n=50, 21-103 years), and related their transcript levels to neurogenic and glial cell markers. Ki67, DCX and both TrkB splice variant mRNAs significantly decreased in the SEZ from infancy to middle age. In contrast, TrkB-TK- mRNA increased in the SEZ from young adulthood into aging, whereas TrkB-TK+ mRNA remained stable. TrkB-TK- mRNA positively correlated with expression of neural precursor (glial fibrillary acidic protein delta and achaete-scute homolog 1) and glial cell markers (vimentin and pan glial fibrillary acidic protein). TrkB-TK+ mRNA positively correlated with expression of neuronal cell markers (DCX and tubulin beta 3 class III). Our results indicate that cells residing in the human SEZ maintain their responsiveness to neurotrophins; however, this capability may change across postnatal life. We suggest that TrkB splice variants may differentially influence neuronal and glial differentiation in the human SEZ