Sex-biased effects on hippocampal circuit development by perinatal SERT expression in CA3 pyramidal neurons
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE214392 | GEO | 2022/10/01
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.
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Project description:to investigate the transcriptional effects on postsynaptic cells following SSRI-like SERT LOF, we used Drosophila mutants for SERT and compared to controls, isolating and profiling Kenyon Cells of the mushroom body
2023-06-26 | GSE227867 | GEO
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Project description:The suppression of fear memory in the absence of danger (fear extinction) requires coordinated neural activity within the amygdala and medial prefrontal (prelimbic and infralimbic) cortex. Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear memory and extinction. In the present study, we investigated the effects of optogenetic manipulations of prelimbic pyramidal neurons on amygdala gene expression to analyze the specific transcriptional pathways involved in fear extinction. To this aim, transgenic mice (Thy1-COP4) having cortical and amygdala pyramidal neurons optogenetically excitable were (or not) fear-conditioned. During the extinction phase, the mice received optogenetic (or sham) stimulations to maintain the activation of the prelimbic pyramidal neurons and impair fear extinction. At the end of behavioral testing, electrophysiological (Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the pyramidal neurons of prelimbic cortex. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Results demonstrate that pyramidal neurons of prelimbic cortex are involved in modulation of the fear responses during extinction phase and their optogenetic stimulation in fear-conditioned mice results in strong modifications of the amygdala transcriptome. Understanding the transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.
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| S-EPMC3878388 | biostudies-literature
Project description:Gray matter volume in the cerebral cortex has been consistently found to be decreased in patients with schizophrenia. The superior temporal gyrus (STG) is one of the cortical regions that exhibit the most pronounced volumetric reduction. This reduction is generally thought to reflect, at least in part, decreased number of synapses; the majority of these synapses are believed to be furnished by glutamatergic axon terminals onto the dendritic spines on pyramidal neurons. Pyramidal neurons in the cerebral cortex exhibit layer-specific connectional properties, providing neural circuit structures that support distinct aspects of higher cortical functions. For instance, dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex are targeted by both local and long-range glutamatergic projections in a highly reciprocal fashion. Synchronized activities of pyramidal neuronal networks, especially in the gamma frequency band (i.e. 30-100 Hz), are critical for the integrity of higher cortical functions. Disturbances of these networks may contribute to the pathophysiology of schizophrenia by compromising gamma oscillation. This concept is supported by the following postmortem and clinical observations. First, the density of dendritic spines on pyramidal neurons in layer 3 of the cerebral cortex, including the STG, have been shown to be significantly decreased by 23-66% in subjects with schizophrenia. Second, consistent with these findings, the average somal area of these pyramidal cells is significantly smaller. Third, we have recently found that, in the prefrontal cortex, the density of glutamatergic axonal boutons, of which dendritic spines are their major targets, was significantly decreased by as much as 79% in layer 3 (but not layer 5) in subjects with schizophrenia. Finally, an increasing number of clinical studies have consistently demonstrated that gamma oscillatory synchrony is profoundly impaired in patients with schizophrenia. Furthermore, gamma impairment has been linked to the symptoms and cognitive deficits of the illness and the severity of these symptoms and deficits have in turn been associated with the magnitude of cortical gray matter reduction. Taken together, understanding the molecular underpinnings of pyramidal cell dysfunction will shed important light onto the pathophysiology of cortical dysfunction of schizophrenia. In order to gain insight into the molecular determinants of pyramidal cell dysfunction in schizophrenia, we combined LCM with Affymetrix microarray and high-throughput TaqManM-BM-.-based MegaPlex qRT-PCR approaches, respectively, to elucidate the alterations in messenger ribonucleic acid (mRNA) and microRNA (miRNA) expression profiles of these neurons in layer 3 of the STG. We found that transforming growth factor beta (TGFM-NM-2) and BMP (bone morphogenetic proteins) signaling pathways and many genes that regulate extracellular matrix (ECM), apoptosis and cytoskeleton were dysregulated in schizophrenia. In addition, we identified 10 miRNAs that were differentially expressed in this illness; interestingly, the predicted targets of these miRNAs included the dysregulated pathways and gene networks identified by microarray analysis. Together these findings provide a neurobiological framework within which we can begin to formulate and test specific hypotheses about the molecular mechanisms that underlie pyramidal cell dysfunction in schizophrenia. Gene epxression microarray from RNA isolated from pyramidal cells in layer III of the STG from 9 normal controls and 9 subjects with schizophrenia. There was no significant difference between diagnosis groups for age, sex, and post mortem interval (PMI).
2012-05-14 | E-GEOD-37981 | biostudies-arrayexpress
Project description:RNA-Seq from CA1 pyramidal neurons purified by FACS from 4-week-old mice.
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