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Analysis of the Cerebral Cortex and Hippocampus Transcriptome Reveals Unique Molecular Changes in the Ts1Cje Mouse Model of Down Syndrome

ABSTRACT: Down syndrome is characterized by a complex phenotype that includes developmental disabilities and congenital anomalies. The molecular origin of these abnormalities is poorly understood. The objective of this study is to analyze whole transcriptome changes in the cortex and hippocampus of the Ts1Cje mouse model of Down syndrome to identify signaling pathways and cellular processes that are consistently perturbed in both brain regions. These pathways will offer a new opportunity for therapeutic interventions to improve cognition in Down syndrome. We refined the translocation breakpoints of MMU12 and MMU16 described previously and established the brain transcriptional map for both monosomic (MMU12) and trisomic (MMU16) regions in Ts1Cje mice. We showed that the hippocampus have more differentially regulated genes, however, the directions of regulation of these genes were generally similar in both brain regions. The secondary genome-wide effect implicated genes known to play major roles in cellular functions that are affected in Down syndrome. Functional analyses highlighted the importance of NFAT signaling, oxidative stress, neuroinflammation, hormone metabolism and olfactory perception via G-protein signaling. This study offers novel targets for therapeutic intervention in Down syndrome.

ORGANISM(S): Mus musculus

PROVIDER: GSE49635 | GEO | 2013/09/05

SECONDARY ACCESSION(S): PRJNA214547

REPOSITORIES: GEO

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Project description:Down syndrome is characterized by a complex phenotype that includes developmental disabilities and congenital anomalies emerging during fetal life. The molecular origin of these abnormalities is poorly understood. Despite the evidence of prenatal onset of the phenotype, most therapeutic trials have been conducted in affected adults. This study presents evidence for fetal brain molecular and neonatal behavioral abnormalities in the Ts1Cje mouse model of Down syndrome. Gene expression changes were more pronounced in the Ts1Cje fetal brains than adult cerebral cortex and hippocampus. Functional pathway analyses showed that Ts1Cje embryonic brains display significant up-regulation of cell cycle and down-regulation of Solute-carrier amino acid transport pathways. Several cellular processes, including apoptosis, inflammation, Jak/Stat signaling, G-protein signaling and oxidoreductase activity were consistently dysregulated at both stages. Fetal brain gene expression changes were associated with early behavioral deficits in surface righting, cliff aversion, negative geotaxis, forelimb grasp, ultrasonic vocalization and homing tests. In combination with the human studies, this suggests that the Down syndrome phenotype manifests prenatally and provides a rationale for prenatal therapy to improve perinatal brain development and postnatal neurocognition. In the present study, we demonstrated that significant gene expression abnormalities were already present in the embryonic day 15 forebrain of the Ts1Cje mouse model of DS. The abnormal Ts1Cje embryonic molecular signature was associated with early postnatal developmental milestones and behavioral changes. These data provide a comprehensive picture of the genotype-phenotype relationship the Ts1Cje model of Down syndrome. We analyzed the forebrain whole transcriptome from embryonic day 15.5 (E15.5) Ts1Cje (n=5) and wild-type (n=5) using Affymetrix mouse gene 1.0 ST array. Data were normalized and analyzed to identify and accurately map genes that are significantly differentially expressed. Functional analyses were performed using GSEA and DAVID and DFLAT to better characterize cellular processes and pathways that are consistently affected in both brain regions. In separate experiments, the Fox scale, ultrasonic vocalization and homing tests were used to investigate postnatal behavioral deficits in Ts1Cje pups (n=29) versus WT littermates (n=64) at days 3 to 21.

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Analysis of the Cerebral Cortex and Hippocampus Transcriptome Reveals Unique Molecular Changes in the Ts1Cje Mouse Model of Down Syndrome

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