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:Sex-biased effects on hippocampal circuit development by perinatal SERT expression in CA3 pyramidal neurons
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Project description:Neurodevelopmental disorders ranging from autism to intellectual disability display sex-biased prevalence and phenotypical presentations. Despite increasing knowledge about temporospatial cortical map development and genetic variants linked to neurodevelopmental disorders, when and how sex-biased neural circuit derailment may arise in diseased brain remain unknown. Here, we identify in mice that serotonin uptake transporter (SERT) in non-serotonergic neurons - hippocampal and prefrontal pyramidal neurons - confers sex-biased effects specifically during neural circuit development. A set of gradient-patterned CA3 pyramidal neurons transiently express SERT to clear extracellular serotonin, coinciding with hippocampal synaptic circuit establishment. Ablating pyramidal neuron SERT (SERTPyramidΔ) alters dendritic spine developmental trajectory in the hippocampus, and precipitates sex-biased impairments in long-term activity-dependent hippocampal synaptic plasticity and cognitive behaviors. Transcriptomic analyses identify sex-biased alterations in gene sets associated with autism, dendritic spine structure, synaptic function and male-specific enrichment of dysregulated genes in glial cells in early postnatal SERTPyramidΔ hippocampus. Our data suggest that SERT function in these pyramidal neurons underscores a temporal- and brain region-specific regulation of normal sex-dimorphic circuit development and a source for sex-biased vulnerability to cognitive and behavioral impairments. This article has an associated 'The people behind the papers' interview.
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Project description:The medial prefrontal cortex (mPFC) is a key brain region involved in controlling working memory, executive function, and self-regulatory behaviours, and its malfunction is a hallmark of several neuropsychiatric disorders such as schizophrenia, depression, and post-traumatic stress disorder. One of the main risk factors for the development of mental illness is chronic stress (CS). Despite some evidence pointing to possible excitation-inhibition (E/I) imbalances caused by CS, the precise mechanism by which CS triggers mPFC dysfunction is not fully understood. Here, using neuroproteomics analysis and whole-cell patch-clamp recordings, we investigated the functional changes in E/I ratio and synaptic drive onto pyramidal neurons and parvalbumin interneurons (PV) in the prelimbic (PL) and infralimbic (IL) cortices, following exposure to 21 days of chronic unpredictable stress. We demonstrate that CS impacts PL- versus IL-pyramidal neurons differently, driving a common decrease in E/I ratio without affecting PV interneurons. Our work brings insightful information and corroborates the hypothesis of stress-induced hypofunction of the mPFC.
2024-10-17 | PXD047291 | Pride
Project description:Impairment in social communication skills is a hallmark feature of autism spectrum disorder (ASD). The role of G-protein coupled receptor 158 (GPR158) in ASD remains largely unexplored. In this study, we observed both constitutive and cell/tissue-specific knockouts of Gpr158 in pyramidal neurons or medial prefrontal cortex (mPFC) result in impaired novelty preference, while sociability remains unaffected in male mice. Notably, loss of GPR158 leads to a significant decline in excitatory synaptic transmission, characterized by the reduction in glutamate vesicles, as well as the expression and phosphorylation of GluN2B in the mPFC. We successfully rescue the phenotype of social novelty deficits either by reintroducing GPR158 in the mPFC of Gpr158 deficient mice or by chemogenetic activation of pyramidal neurons where Gpr158 is specifically ablated. Our findings indicate that GPR158 in pyramidal neurons plays a specific role in modulating social novelty, and may represent a potential target for treating social disorder.
2024-09-04 | GSE276304 | GEO
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.
2017-11-08 | GSE93534 | GEO
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 | GSE227866 | GEO
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
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.
2021-01-14 | GSE162417 | GEO
Project description:Chronic pain is a major health care problem with great social and economic consequences. Although the medial prefrontal cortex (mPFC) and the thalamus have been implicated in regulating pain, whether and how these regions may involve in pain chronification process have remained largely unknown. Here, we show that Foxp2+ neurons in mPFC, which are corticothalamic (CT) neurons representing the major mPFC output to thalamus, are deactivated in chronic inflammatory pain. Interestingly, prolonged, but not short-term, inactivation of the Foxp2+ neurons in mPFC increases the sensitivity to noxious stimulations. Conversely, chemogenetic activation of this neuronal cluster induces robust antinociceptive effects in both naïve mice and mice with chronic inflammatory pain. Furthermore, we found that the mPFC Foxp2+ neurons project to several thalamic relay nuclei and that activation of the mPFC to the parataenial nucleus of thalamus (PTN) circuit relieves pain. Finally, RNA-seq of the mPFC Foxp2+ neurons revealed that many genes related to neuronal activity are dysregulated in mice with chronic inflammatory pain. Collectively, our studies revealed that Foxp2+ neurons in mPFC that project to thalamus play a critical role in somatosensory processing and pain chronification.
2023-09-16 | GSE243136 | GEO
Project description:The hippocampal CA3 region is essential for pattern completion and generation of sharp-wave ripples. During these operations, coordinated activation of ensembles of CA3 pyramidal neurons produces spatiotemporally structured input patterns arriving onto dendrites of recurrently connected CA3 neurons. To understand how such input patterns are translated into specific output patterns, we characterized dendritic integration in CA3 pyramidal cells using two-photon imaging and glutamate uncaging. We found that thin dendrites of CA3 pyramidal neurons integrate synchronous synaptic input in a highly supralinear fashion. The amplification was primarily mediated by NMDA receptor activation and was present over a relatively broad range of spatiotemporal input patterns. The decay of voltage responses, temporal summation, and action potential output was regulated in a compartmentalized fashion mainly by a G-protein-activated inwardly rectifying K(+) current. Our results suggest that plastic dendritic integrative mechanisms may support ensemble behavior in pyramidal neurons of the hippocampal circuitry.
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