Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA151825 | ENA |
REPOSITORIES: ENA
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Project description:The immense molecular diversity of neurons challenges our ability to deconvolve the relationship between the genetic and the cellular underpinnings of neuropsychiatric disorders. We suspected that comprehensive approaches to parsing this complexity may inform human genetics studies. The serotonergic system has long been suspected in disorders that involve repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit the in vivo profiling of all ongoing translation in serotonergic neurons. From this, we identified 174 serotonergic-cell enriched and specific genes, including all known markers of these cells. Analysis of common variants in these genes in human families with autism implicated two genes, C1QTNF2 and the RNA-binding protein CELF6. This work provides a reproducible and accurate method to assess the translational profiles of serotonergic neurons under a variety of conditions in vivo, and suggests cell-specific information may provide some insight into the genetic etiology of complex psychiatric disorders
2012-12-31 | GSE36068 | GEO
Project description:The immense molecular diversity of neurons challenges our ability to deconvolve the relationship between the genetic and the cellular underpinnings of neuropsychiatric disorders. We suspected that comprehensive approaches to parsing this complexity may inform human genetics studies. The serotonergic system has long been suspected in disorders that involve repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit the in vivo profiling of all ongoing translation in serotonergic neurons. From this, we identified 174 serotonergic-cell enriched and specific genes, including all known markers of these cells. Analysis of common variants in these genes in human families with autism implicated two genes, C1QTNF2 and the RNA-binding protein CELF6. This work provides a reproducible and accurate method to assess the translational profiles of serotonergic neurons under a variety of conditions in vivo, and suggests cell-specific information may provide some insight into the genetic etiology of complex psychiatric disorders For each cell population, three independent TRAP replicates were collected, and total RNA from both the immunoprecipitate and unbound fractions were seperately amplified and hybridized. For each tissue, several representative unnbound fractions are provided to serve as controls. Biological replicates are GCRMA normalized within groups. Following averaging of replicates, we recommend further global normalization between groups, using affymetrix biotinylated controls, to correct for any broad biases in scanning and hybridization. Finally for many analyses, we also recommend filtering to remove those probesets with low IP/UB fold change values from each cell type(see PMID:20962086). Researchers can contact us for spreadsheets where these additional steps have been completed.
2012-12-31 | E-GEOD-36068 | biostudies-arrayexpress
Project description:Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes psychosocial stress vulnerability in mouse. This occurs through dysfunction of type 1A serotonin (5-hydroxytryptamine, 5-HT) receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knockout (D2LR-KO) male mice as compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT release in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was up-regulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR–activated G-protein–activated inwardly rectifying potassium (GIRK) conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Taken together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.
2019-01-09 | GSE124806 | GEO
Project description:<p><strong>Background:</strong> Autism spectrum disorder (ASD) is biologically heterogeneous and has limited mechanism-informed interventions targeting core behavioral symptoms. Emerging evidence suggests that gut microbial metabolism shapes neurobehavioral outcomes, yet the specific metabolic pathways linking gut ecology to brain function remain incompletely understood. One candidate pathway is polyamine metabolism, which links microbial amino acid metabolism to host regulation and represents a plausible but underexplored contributor to ASD-related phenotypes. Notably, the psychobiotic <em>Lactiplantibacillus plantarum</em> PS128 has been reported to improve social behaviors in individuals with ASD, although the molecular basis for these effects is unclear. In this study, we used Fragile X mental retardation 1 knockout (<em>Fmr1</em> KO) mice, a well-established ASD model, to investigate microbiota-dependent metabolic mechanisms underlying autism-like behaviors. </p><p><strong>Results:</strong> We found that autism-like behaviors in<em> Fmr1</em> KO mice were associated with gut dysbiosis, impaired intestinal barrier integrity, disruption of the arginine–ornithine–polyamine pathway, and elevated putrescine in the prefrontal cortex (PFC). Supplementation with PS128 remodeled the gut microbiota, reduced inflammation- and disease-associated taxa, improved intestinal structure and permeability, and restored polyamine homeostasis. Targeted metabolomics revealed an increased PFC-to-serum putrescine ratio in KO mice, which was normalized following PS128 intervention. This correction was accompanied by reduced expression of polyamine transporters in the PFC, including ATP13A family members. Causal experiments supported a functional role for putrescine, as peripheral elevation of putrescine induced autism-like behaviors in wild-type mice, whereas pharmacological inhibition of putrescine synthesis ameliorated behavioral deficits in <em>Fmr1</em> KO mice.</p><p><strong>Conclusions: </strong>These findings identify putrescine metabolic dysregulation as a key contributor to autism-like phenotypes and support the existence of an ASD subtype defined by disruption of the arginine–ornithine–polyamine axis. Integrated multi-omics and causal perturbation analyses support a model in which microbiota-targeted intervention rebalances systemic polyamine regulation along the gut–brain axis, thereby improving ASD-relevant behaviors. Our work provides mechanistic evidence linking microbial metabolism to neurochemical homeostasis and highlights the translational potential of metabolic stratification in ASD.</p><p><br></p><p><strong>UHPLC-MS/MS</strong> analysis of murine <strong>brain</strong> <strong>tissues </strong>are reported in this study</p><p><strong>GC-MS</strong> analysis of murine <strong>brain</strong> <strong>tissues</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13859' rel='noopener noreferrer' target='_blank'><strong>MTBLS13859</strong></a></p><p><strong>UHPLC-MS/MS</strong> analysis of murine <strong>blood serum</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13862' rel='noopener noreferrer' target='_blank'><strong>MTBLS13862</strong></a></p>
2026-02-10 | MTBLS13881 | MetaboLights
Project description:<p><strong>Background </strong>Autism spectrum disorder (ASD) is biologically heterogeneous and has limited mechanism-informed interventions targeting core behavioral symptoms. Emerging evidence suggests that gut microbial metabolism shapes neurobehavioral outcomes, yet the specific metabolic pathways linking gut ecology to brain function remain incompletely understood. One candidate pathway is polyamine metabolism, which links microbial amino acid metabolism to host regulation and represents a plausible but underexplored contributor to ASD-related phenotypes. Notably, the psychobiotic Lactiplantibacillus plantarum PS128 has been reported to improve social behaviors in individuals with ASD, although the molecular basis for these effects is unclear. In this study, we used Fragile X mental retardation 1 knockout (Fmr1 KO) mice, a well-established ASD model, to investigate microbiota-dependent metabolic mechanisms underlying autism-like behaviors. </p><p><strong>Results </strong>We found that autism-like behaviors in Fmr1 KO mice were associated with gut dysbiosis, impaired intestinal barrier integrity, disruption of the arginine–ornithine–polyamine pathway, and elevated putrescine in the prefrontal cortex (PFC). Supplementation with PS128 remodeled the gut microbiota, reduced inflammation- and disease-associated taxa, improved intestinal structure and permeability, and restored polyamine homeostasis. Targeted metabolomics revealed an increased PFC-to-serum putrescine ratio in KO mice, which was normalized following PS128 intervention. This correction was accompanied by reduced expression of polyamine transporters in the PFC, including ATP13A family members. Causal experiments supported a functional role for putrescine, as peripheral elevation of putrescine induced autism-like behaviors in wild-type mice, whereas pharmacological inhibition of putrescine synthesis ameliorated behavioral deficits in Fmr1 KO mice.</p><p><strong>Conclusions </strong>These findings identify putrescine metabolic dysregulation as a key contributor to autism-like phenotypes and support the existence of an ASD subtype defined by disruption of the arginine–ornithine–polyamine axis. Integrated multi-omics and causal perturbation analyses support a model in which microbiota-targeted intervention rebalances systemic polyamine regulation along the gut–brain axis, thereby improving ASD-relevant behaviors. Our work provides mechanistic evidence linking microbial metabolism to neurochemical homeostasis and highlights the translational potential of metabolic stratification in ASD. </p><p><br></p><p><strong>GC-MS</strong> analysis of murine <strong>brain tissues</strong> are reported in in this study</p><p><strong>UHPLC-MS/MS</strong> analysis of murine <strong>brain tissues</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13881' rel='noopener noreferrer' target='_blank'><strong>MTBLS13881</strong></a></p><p><strong>UHPLC-MS/MS </strong>analysis of murine <strong>blood serum</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13862' rel='noopener noreferrer' target='_blank'><strong>MTBLS13862</strong></a></p>
2026-02-06 | MTBLS13859 | MetaboLights
Project description:<p class='ql-align-justify'><strong>Background</strong>: Autism spectrum disorder (ASD) is biologically heterogeneous and has limited mechanism-informed interventions targeting core behavioral symptoms. Emerging evidence suggests that gut microbial metabolism shapes neurobehavioral outcomes, yet the specific metabolic pathways linking gut ecology to brain function remain incompletely understood. One candidate pathway is polyamine metabolism, which links microbial amino acid metabolism to host regulation and represents a plausible but underexplored contributor to ASD-related phenotypes. Notably, the psychobiotic <em>Lactiplantibacillus plantarum</em> PS128 has been reported to improve social behaviors in individuals with ASD, although the molecular basis for these effects is unclear. In this study, we used Fragile X mental retardation 1 knockout (<em>Fmr1</em> KO) mice, a well-established ASD model, to investigate microbiota-dependent metabolic mechanisms underlying autism-like behaviors.</p><p class='ql-align-justify'><strong>Results</strong>: We found that autism-like behaviors in <em>Fmr1</em> KO mice were associated with gut dysbiosis, impaired intestinal barrier integrity, disruption of the arginine-ornithine-polyamine pathway, and elevated putrescine in the prefrontal cortex (PFC). Supplementation with PS128 remodeled the gut microbiota, reduced inflammation- and disease-associated taxa, improved intestinal structure and permeability, and restored polyamine homeostasis. Targeted metabolomics revealed an increased PFC-to-serum putrescine ratio in KO mice, which was normalized following PS128 intervention. This correction was accompanied by reduced expression of polyamine transporters in the PFC, including ATP13A family members. Causal experiments supported a functional role for putrescine, as peripheral elevation of putrescine induced autism-like behaviors in wild-type mice, whereas pharmacological inhibition of putrescine synthesis ameliorated behavioral deficits in <em>Fmr1</em> KO mice.</p><p class='ql-align-justify'><strong>Conclusions</strong>: These findings identify putrescine metabolic dysregulation as a key contributor to autism-like phenotypes and support the existence of an ASD subtype defined by disruption of the arginine-ornithine-polyamine axis. Integrated multi-omics and causal perturbation analyses support a model in which microbiota-targeted intervention rebalances systemic polyamine regulation along the gut-brain axis, thereby improving ASD-relevant behaviors. Our work provides mechanistic evidence linking microbial metabolism to neurochemical homeostasis and highlights the translational potential of metabolic stratification in ASD.</p><p class='ql-align-justify'><br></p><p><strong>UHPLC-MS/MS</strong> analysis of murine <strong>blood serum</strong> are reported in this study</p><p><strong>UHPLC-MS/MS</strong> analysis of murine<strong> brain tissues</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13881' rel='noopener noreferrer' target='_blank'><strong>MTBLS13881</strong></a></p><p class='ql-align-justify'><strong>GC-MS </strong>analysis of murine <strong>brain tissues</strong> are reported in <a href='https://www.ebi.ac.uk/metabolights/MTBLS13859' rel='noopener noreferrer' target='_blank'><strong>MTBLS13859</strong></a></p>
2026-02-07 | MTBLS13862 | MetaboLights
Project description:One of the most fundamental challenges in developing treatments for autism-spectrum disorders is the heterogeneity of the condition. More than one hundred genetic mutations confer high risk for autism, with each individual mutation accounting for only a small fraction of autism cases. Subsets of risk genes can be grouped into functionally-related pathways, most prominently synaptic proteins, translational regulation, and chromatin modifications. To possibly circumvent this genetic complexity, recent therapeutic strategies have focused on the neuropeptides oxytocin and vasopressin which regulate aspects of social behavior in mammals. However, whether genetic risk factors might predispose to autism due to modification of oxytocinergic signaling remains largely unknown. Here, we report that an autism-associated mutation in the synaptic adhesion molecule neuroligin-3 (Nlgn3) results in impaired oxytocin signaling in dopaminergic neurons and in altered social novelty responses in mice. Surprisingly, loss of Nlgn3 is accompanied by a disruption of translation homeostasis in the ventral tegmental area. Treatment of Nlgn3KO mice with a novel, highly specific, brain-penetrant inhibitor of MAP-kinase interacting kinases resets mRNA translation and restores oxytocin and social novelty responses. Thus, this work identifies an unexpected convergence between the genetic autism risk factor Nlgn3, translational regulation, and oxytocinergic signaling. Focus on such common core plasticity elements might provide a pragmatic approach to reduce the heterogeneity of autism phenotypes. Ultimately, this would allow for mechanism-based stratification of patient populations to increase the success of therapeutic interventions.
2020-04-27 | PXD018808 | Pride
Project description:Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
2023-07-20 | PXD041769 | Pride
Project description:The amygdala is a prominent region of the brain processing stress-related emotion and vigilance. Additionally it is known that the serotonergic system is strongly involved in stress response and adaptation. The serotonin transporter (5-HTT) as key regulator of serotonergic activity in the brain is associated with stress-related neuropsychiatric disorders as well as heightened trait anxiety/dysphoria and exaggerated response to fear and environmental stress in humans. Also 5-HTT knockout mice display increased anxiety- and depression-related behaviors, altered stress reactivity and stress-coping abilities, gene expression differences and altered dendritic morphology. We measured immediate reactions to an acute stressor in 5-HTT knockout mice vs. wildtypes using microarrays for genome wide gene expression profiling in the amygdala and identified different functional clusters dependent on condition and genotype. Global amygdalar gene expression profiles were compared between 5-HTT knockout vs. wildtype mice in the conditions control vs. acute stressor in a total sample of 20 (5 biological replicates per genotype and condition).
2013-03-13 | E-GEOD-40393 | biostudies-arrayexpress
Project description:Social deficits and repetitive behaviors define autism spectrum disorder (ASD), yet their shared underlying mechanisms remain elusive. Here we uncover a convergent pathophysiological mechanism across multiple ASD models. We found that GABAergic neurons in the dorsal raphe nucleus (DRNGABA neurons) are hyperactive in Shank3B–/– mice. Chemogenetic activation of these neurons recapitulated ASD-like behaviors, whereas inhibition reversed them. Shank3 knockdown in DRNGABA neurons phenocopied ASD-related changes through upregulation of ErbB4-mGluR1/5 signaling. Sustained DRNGABA hyperactivity drove the pathological recruitment of postsynaptic GABAA α3 receptors, resulting in hypoactivity of DRN5-HT neurons. Gabra3 knockdown in DRN5-HT neurons rescued behavioral deficits in Shank3B–/– mice. Notably, systemic low-dose bicuculline—selectively inhibiting GABAA α3 receptors—ameliorated core ASD-like behaviors across multiple etiologically distinct models, including Shank3B–/– mice, offspring of Poly: IC-injected dams, and BTBR mice, without affecting basal transmission. Together, these findings identify pathologically activated GABAA α3 receptors as a convergent therapeutic target for ASD.
2026-03-27 | PXD076235 |