CYFIP1 dosages exhibit divergent behavioral impact via diametric regulation of NMDAR complex translation in mouse models of psychiatric disorders
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA702462 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13731708.fastq.gz | Fastqsanger.gz | |||
| SRR13731709.fastq.gz | Fastqsanger.gz | |||
| SRR13731710.fastq.gz | Fastqsanger.gz | |||
| SRR13731711.fastq.gz | Fastqsanger.gz | |||
| SRR13731712.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 5 |
Similar Datasets
Project description:Gene dosage imbalance caused by copy number variations (CNVs) are prominent contributors to brain disorders. 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), respectively. The mechanism underlying these diametric contributions remain unclear. Here we established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs and these mice exhibited both distinct and shared behavioral abnormalities related to ASD and SCZ. RIP-seq analysis identified mRNA targets of CYFIP1 in vivo, including postsynaptic NMDAR complex components. These mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses due to dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in mouse models with diametric CYFIP1 dosages rescues behavioral abnormalities. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.
2022-02-02 | GSE166939 | GEO
Project description:Importin α4, which is encoded by the Kpna4 gene, is a well characterized nuclear-cytoplasmic transport factor known to mediate transport of transcription factors including NF-κB. Here, we report that Kpna4 knock-out (KO) mice exhibit psychiatric disorder-related behavioral abnormalities such as anxiety-related behaviors, deceased social interaction and sensorimotor gating deficits. Contrary to a previous study predicting attenuated NF-κB activity as a result of Kpna4 deficiency, we observed a significant increase in expression levels of NF-κB genes and pro-inflammatory cytokines such as TNFα, Il1β or Il-6 in the Prefrontal Cortex or Basolateral Amygdala of the KO mice. Moreover, examination of inflammatory responses in primary cells revealed that Kpna4 deficient cells have an increased inflammatory response, which was rescued by addition of not only full-length, but also a nuclear transport deficient truncation mutant of importin α4, suggesting contribution of its non-transport functions. Furthermore, RNAseq of sorted adult Microglia and Astrocytes and subsequent transcription factor analysis suggested increases in Polycomb repressor complex 2 (PRC2) activity in Kpna4 KO cells. Taken together, importin α4 deficiency induces psychiatric disorder-related behavioral deficits in mice, along with an increased inflammatory response and possible alteration of PRC2 activity in glial cells.
2024-04-18 | GSE264180 | GEO
Project description:Genetic linkage analysis suggested that GKAP, a scaffold protein of the NMDA receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine cancer (PanNET). Here we establish that GKAP governs invasive growth and treatment response of PanNET via its pivotal role in regulating the NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we distilled gene expression signatures orchestrated by the NMDAR-GKAP axis, in addition to identifying two downstream effectors FMRP and HSF-1. Additionally, GKAP, FMRP, and HSF1 are functionally implicated in invasiveness of pancreatic ductal adenocarcinoma. Finally, gene expression signatures in tumors with low NMDAR activity are significantly associated with favorable patient prognosis in several cancer types.
2018-04-18 | GSE102598 | GEO
Project description:The study revealed differentially expressed lncRNAs in synaptic and extrasynaptic NMDAR activation and suggested that lncRNAs might be responsible for extrasynaptic NMDAR-induced neurodegeneration
2018-07-07 | GSE116735 | GEO
Project description:Abnormal N-methyl-D-aspartate receptor (NMDAR) function has been implicated in the pathophysiology of schizophrenia. D-serine is an important NMDAR modulator, and to elucidate the role of the D-serine synthesis enzyme serine racemase (Srr) in schizophrenia, we identified and characterized mice with an ENU-induced mutation that results in a complete loss of Srr activity and drastically reduced D-serine levels. Mutant mice displayed behaviors relevant to schizophrenia, including impairments in prepulse inhibition, sociability and spatial discrimination. Behavioral deficits were rescued by D-serine and the atypical antipsychotic clozapine, and were conversely, amplified by NMDAR inhibition. Expression profiling revealed that the Srr mutation influenced several genes that have been linked to schizophrenia and cognitive ability. Furthermore, analysis of Srr genetic variants in humans identified a robust association with schizophrenia. This study demonstrates that aberrant serine racemase function and diminished D-serine may contribute to schizophrenia pathogenesis, and that D-serine may be a beneficial form of treatment Keywords: genetic-mutant vs. wildtype comparison
2009-09-05 | GSE13974 | GEO
Project description:Purpose: To identify significantly differentially expressed genes and to investigate the intricate molecular regulatory network underlying anti-NMDA receptor encephalitis associated with ovarian teratoma. Methods: This retrospective study analyzed ovarian teratoma samples from patients with and without NMDAR-E. We employed RNA sequencing for gene expression profiling. qPCR and Western blotting were used for gene and protein expression validation. Results: We identified 2524 significantly differentially expressed genes. The changes were notable in mRNA levels in ovarian teratomas associated with NMDAR-E. Functional enrichment analysis highlighted extracellular matrix and immune activation pathways. Key genes and proteins involved in ferroptosis and immune activation, including SLC40A1, GGH, FKBP11, CCDC80, and ANK3, showed significant expression differences.Conclusions: Our findings offer deeper insights into the pathophysiology of NMDAR-encephalitis associated with ovarian teratomas. The identified biomarkers, particularly in ferroptosis and immune activation pathways, provide potential targets for diagnosis and treatment.
2024-12-19 | GSE277739 | GEO
Project description:BackgroundGene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear.MethodsWe established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo.ResultsCyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities.ConclusionsCYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.
| S-EPMC8568734 | biostudies-literature
Project description:Topoisomerase 3b (Top3b) is the only dual-activity topoisomerase in animals that can change topology for both DNA and RNA, and facilitate transcription on DNA and translation on mRNAs. Top3b mutation has been linked to schizophrenia, autism, epilepsy, and cognitive impairment. However, whether and how Top3b mutations are causal to these disorders remain unclear. Here we show that Top3b knockout mice exhibit behavioral phenotypes related to psychiatric disorders and cognitive impairment, including increased anxiety and fear, abnormal social interactions, impaired context discrimination, and defective spatial learning and memory. In addition, these mice display deficits in adult hippocampal neurogenesis and synaptic plasticity. Notably, the brains of the mutant mice exhibit impaired global neuronal activity-dependent transcription in response to fear conditioning stress, and the affected genes include many that are critical for neuronal functions and mental health. Our data suggest that Top3b is essential for normal brain function in multiple domains, and defective neuronal activity-dependent transcription may be a mechanism by which Top3b deletion causes cognitive impairment and psychiatric disorders.
2020-05-22 | GSE145730 | GEO
Project description:Maternal malnutrition remains one the major early-life adversities contributing poor health in one in five children worldwide. Clinical studies demonstrate that malnourished children are growth-impaired, exhibit behavioral changes and suffer from cognitive impairments. These health effects can persist even if nutrition becomes adequate later in life. Experimental studies on rodents have shown that maternal protein restriction is associated with the emergence of several adverse effects of offspring neurological development. In addition, reported effects of prenatal and/or postnatal protein malnutrition on the offspring include changes in exploratory behavior and anxiety, altered learning and memory abilities and a different response to aversive stimuli. These behavioral alterations characterize the symptoms of various psychiatric disorders that has been increasingly regarded as developmental disorders. Social behavioral deficits in psychiatric diseases have been hypothesized to arise form elevation in the cellular balance of excitation and inhibition within the cortex generally, and PFC specifically. Such imbalance may be caused either by increased activity in excitatory neurons or by reduction in inhibitory neuron function. Interestingly, decreases in inhibitory neurotransmission are a common finding in animal models of ASD. In addition, direct alterations of E/I balance within the PFC in adult mice have strong effect on social motivation. The critical question we have posed in this work is whether maternal protein malnutrition alters the offspring’s social cognition and if this were the case, if these behavioral deficits are transmitted to the following generation. We hypothesized that at the basis of such alterations in social cognition underlie changes in gene expression related to E/I signaling within the mPFC. Our results focus on damaging effects of maternal protein malnutrition even for generations that are not exposed to this environmental adversity.
2025-08-25 | GSE156887 | GEO
Project description:To investigate the changes of the transcriptome in neuronal cells under the condition of NMDAR hypofunction and H/R injury, we compared the changes of mRNA and lncRNA expression levels in mouse hippocampal neuron HT22 cell with or without NMDAR knockdown and H/R stimulation by RNA sequencing.
2022-10-10 | GSE214716 | GEO