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MicroRNAs and gene-environment interactions in autism: effects of prenatal maternal stress and the SERT gene on maternal microRNA expression

ABSTRACT: In the study presented here, microRNA expression was profiled in blood samples from mothers of children with autism, with known stress exposure during pregnancy. 2500 mature microRNAs were examined. Thirty-four maternal blood samples were examined in this study. Samples were divided into five groups based on maternal SERT genotypes (LL/LS/SS) and prenatal stress level (High/Low).

ORGANISM(S): Homo sapiens

PROVIDER: GSE179222 | GEO | 2021/07/02

REPOSITORIES: GEO

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Project description:The serotonin transporter (SERT, SLC6A4), belonging to Na+ and Cl- dependent transporters, functions to regulate the availability of serotonin (5-HT) in various tissues including brain, platelets, and intestine. Alterations in 5-HT levels and/or SERT expression have been implicated in pathophysiological conditions including anxiety-like behavior, obesity, cardiovascular disorders and GI disorders such as IBD, IBS, and diarrhea. Accordingly, SERT deficiency in mice is pleiotropic with many different phenotypic traits. Transgenic mice with global deletion of SERT exhibit increased anxiety, abnormal GI motility, and obesity associated with hyperglycemia. Additionally, these mice are more susceptible to intestinal inflammation. The mechanism by which SERT deficiency underlies GI related disturbances and exacerbates the severity of gut inflammation is not known. Thus, we evaluated the ileal mRNA expression to identify potential intestinal targets that contribute to disease pathogenesis when the SERT gene is non-functional. For these studies, RNA was extracted from ileum mucosa from age matched (9-10 wk) control and SERT KO mice by Trizol and was subjected to Mouse mRNA and OneArray Profiling. Our microarray data revealed 492 significantly upregulated and 293 downregulated genes in SERT KO ileum. Pathway analysis revealed significant enrichment in cell cycle, signaling, chemotaxis, and epithelial transporters. Genes of interest were validated by RT-PCR, which included CYP1A1 (~20 fold decrease, p < 0.05), CLDN8 (~30% decrease, p < 0.05), and HMGCS2 (~7 fold increase, p < 0.05). Similar changes were found in colon. A remarkable decrease in expression of Cyp1a1, which encodes a cytochrome P450 enzyme, provides a novel role of serotonergic pathways in drug and xenobiotic detoxification. CLDN8 encodes for claudin 8, which is downregulated in patients with Crohn’s disease. Deficiency of HMGCS2, the mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase, is linked to hypoglycemia. Our data provides novel clues for differential expression of genes affected by 5-HT and/or SERT deficiency in the intestine.

Project description:Coordinated gene expression changes across the CNS help to produce the mammalian maternal phenotype. Lateral septum (LS) is a brain region critically involved with aspects of maternal care, and we recently examined gene expression of whole septum (LS and medial septum) in selectively bred maternal mice. Here, we expand on the prior study by 1) conducting microarray analysis solely on LS in virgin and postpartum mice, 2) using outbred mice, and 3) evaluating the role of sensory input on gene expression changes. Large scale changes in genes related to neuronal signaling were identified, including nine GABAA receptor subunits (p<0.05). Subunits ?4 and ? were downregulated in maternal LS, likely reflecting a reduction in the extrasynaptic, neurosteroid-sensitive ?4/? containing receptor subtype. Conversely, subunits ? and ? were increased in maternal LS. Sixteen K+ channel related genes showed altered expression, as did dopamine receptors Drd1a and Drd2 (both downregulated), hypocretin receptor 1 (Hcrtr1), kappa opioid receptor 1 (Oprk1), and transient receptor potential channel 4 (Trpc4). Expression of a large number of genes linked to developmental processes or cell differentiation were also altered in postpartum LS, including chemokine (C-X-C) motif ligand 12 (Cxcl12), fatty acid binding protein 7 (Fabp7), plasma membrane proteolipid (Pllp), and suppressor of cytokine signaling 2 (Socs2). Additional genes that are linked to anxiety, such as glutathione reductase (Gsr), exhibited altered expression. Pathway analysis also identified changes in genes related to cyclic nucleotide metabolism, chromatin structure, and the Ras gene family. The sensory presence of pups was found to contribute to the altered expression of a subset of genes across all categories. This study suggests that both large changes in neuronal signaling and the possible terminal differentiation of neuronal and/or glial cells play important roles in producing the maternal state. In total, 18 total RNA samples derived from microdissected lateral septum were used for microarray analysis: 6 samples from lactating maternal mice (maternal), 6 samples from maternal mice that have had their pups removed (pups removed), and 6 samples from age-matched virgin mice (virgin). All samples are biological replicates.

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MicroRNAs and gene-environment interactions in autism: effects of prenatal maternal stress and the SERT gene on maternal microRNA expression

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