Browsing by Subject "Dorsolateral prefrontal cortex"

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    Dynamic alternative splicing events in the dorsolateral prefrontal cortex during adolescence-young adulthood period and implications for schizophrenia
    (2020-11) Çelikbaş, Kübra
    Alternative splicing (AS) or differential exon usage (DEU) is a regular process after gene expression and it contributes to the diversity of the genome by generating multiple protein isoforms. According to recent studies, the majority (92-94%) of all human multi-exon genes undergo AS and the brain, especially the neocortex, has the highest number of AS events compared to other tissues. While contributing to the complexity of the brain, AS may lead to neuropsychiatric disorders such as schizophrenia or autism if dysregulated. Adolescence and young adulthood (AYA) period which nearly covers age range between 15 to 24 years old, is known to be a critical time to develop several neuropsychiatric disorders including schizophrenia and depression. Therefore, it is important to know developmental changes in AS events that occur in healthy brains in order to understand what is disrupted in a diseased brain. Although there are many studies investigating the possible roles of AS in the function of specific neuron types and during neurogenesis, there are only a few studies investigating AS changes in the human brain during different developmental periods. Therefore, in this study we first compared DEU that occur in the dorsolateral prefrontal cortex (DLPFC) of psychologically healthy individuals during AYA period to other developmental periods: infancy, early childhood, middle and late childhood, young adulthood, middle adulthood, and late adulthood. Additionally we compared DEU that occur in the DLPFC of schizophrenia patients to psychologically healthy individuals. Then we found exons that show both developmental and schizophrenia related DEU changes. Our results revealed 4 exons that belong to 3 different genes: AKAP7, BAIAP3 and SEMA3B. If further investigated, these exons can help us better understand the pathophysiology of schizophrenia and be possible early markers of the disease.
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    Whole-genome and RNA sequencing reveal variation and transcriptomic coordination in the developing human prefrontal cortex
    (Elsevier, 2020-04) Werling, D. M.; Pochareddy, S.; Choi, J.; An, J.-Y.; Sheppard, B.; Peng, M.; Li, Z.; Dastmalchi, C.; Santpere, G.; Sousa, A. M. M.; Tebbenkamp, A. T. N.; Kaur, N.; Gulden, F. O.; Breen, M. S.; Liang, L.; Gilson, M. C.; Zhao, X.; Dong, S.; Klei, L.; Çiçek, A. Ercüment; Buxbaum, J. D.; Adle-Biassette, H.; Thomas, J.-L.; Aldinger, K. A.; O’Day, D. R.; Glass, I. A.; Zaitlen, N. A.; Talkowski, M. E.; Roeder, K.; State, M. W.; Devlin, B.; Sanders, S. J.; Sestan, N.
    Gene expression levels vary across developmental stage, cell type, and region in the brain. Genomic variants also contribute to the variation in expression, and some neuropsychiatric disorder loci may exert their effects through this mechanism. To investigate these relationships, we present BrainVar, a unique resource of paired whole-genome and bulk tissue RNA sequencing from the dorsolateral prefrontal cortex of 176 individuals across prenatal and postnatal development. Here we identify common variants that alter gene expression (expression quantitative trait loci [eQTLs]) constantly across development or predominantly during prenatal or postnatal stages. Both “constant” and “temporal-predominant” eQTLs are enriched for loci associated with neuropsychiatric traits and disorders and colocalize with specific variants. Expression levels of more than 12,000 genes rise or fall in a concerted late-fetal transition, with the transitional genes enriched for cell-type-specific genes and neuropsychiatric risk loci, underscoring the importance of cataloging developmental trajectories in understanding cortical physiology and pathology.
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    Working memory in unaffected relatives of patients with schizophrenia: a meta-analysis of functional magnetic resonance imaging studies
    (Oxford University Press, 2016) Zhang, R.; Picchioni, M.; Allen, P.; Toulopoulou, T.
    Working memory deficits, a core cognitive feature of schizophrenia may arise from dysfunction in the frontal and parietal cortices. Numerous studies have also found abnormal neural activation during working memory tasks in patients' unaffected relatives. The aim of this study was to systematically identify and anatomically localize the evidence for those activation differences across all eligible studies. Fifteen functional magnetic resonance imaging (fMRI) manuscripts, containing 16 samples of 289 unaffected relatives of patients with schizophrenia, and 358 healthy controls were identified that met our inclusion criteria: (1) used a working memory task; and (2) reported standard space coordinates. Activation likelihood estimation (ALE) identified convergence across studies. Compared to healthy controls, patients' unaffected relatives showed decreases in neural activation in the right middle frontal gyrus (BA9), as well as right inferior frontal gyrus (BA44). Increased activation was seen in relatives in the right frontopolar (BA10), left inferior parietal lobe (BA40), and thalamus bilaterally. These results suggest that the familial risk of schizophrenia is expressed in changes in neural activation in the unaffected relatives in the cortical-subcortical working memory network that includes, but is not restricted to the middle prefrontal cortex.