Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CYFIP1 dosages exhibit divergent behavioral impact via diametric regulation of NMDAR complex translation in mouse models of psychiatric disorders

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE166939 | GEO | 2022/02/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

hCyfip1 overexpression in the basolateral amygdala of mice

Project description:CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is over-expressed in Dup15q syndrome as well as autism spectrum disorder (ASD). While CYFIP1 heterozygosity has been rigorously studied due to its loss in 15q11.2 deletion, Prader-Willi and Angelman syndrome, the effects of CYFIP1 over-expression, as is observed in patients with CYFIP1 duplication are less well understood. Here, we developed a mouse model of human CYFIP1 overexpression (CYFIP1 OE) to study the effects of excess CYFIP1 on rodent behavior and biological pathways. Extensive behavioral testing of CYFIP1 OE mice reveals no changes in the core behaviors related to ASD: social interactions and repetitive behaviors. However, we did observe mild learning deficits and an exaggerated fear response. Using RNA sequencing of the basolateral amygdala, a region associated with fear response, we observed changes in pathways related to cytoskeletal regulation, oligodendrocytes and myelination. We also identified GABA-A subunit composition changes in BLA neurons which are part of the fear conditioning neuronal circuit. Overall, this research identifies the behavioral and molecular consequences of CYFIP1 overexpression and how they contribute to the variable phenotype seen in Dup15q syndrome and in ASD patients with excess CYFIP1.

2020-07-29 | GSE125697 | GEO

CYFIP1 dosages exhibit divergent behavioral impact via diametric regulation of NMDAR complex translation in mouse models of psychiatric disorders

Project description:CYFIP1 dosages exhibit divergent behavioral impact via diametric regulation of NMDAR complex translation in mouse models of psychiatric disorders

| PRJNA702462 | ENA

Zbtb16 regulates social cognitive behaviors and neocortical development

Project description:Recent genomic studies suggest that a single gene is involved in multiple diseases, however it is unclear what mechanism destined for different diseases by a single gene. Mutations of ZBTB16 are associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), but how ZBTB16 fates ASD or SCZ are unknown. Here we show the deletion of Zbtb16 in mice leads to both ASD- and SCZ-like behaviors such as social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we carried out histological studies and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in the prefrontal cortex (PFC) of Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the PFC of Zbtb16 KO mice. Using a genomics approach, we identified the Zbtb16-transcriptome that includes genes involved in both ASD and SCZ pathophysiology and neocortical maturation such as neurogenesis and myelination. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the differential role of the single gene ZBTB16 in ASD and SCZ.

2021-05-12 | GSE155424 | GEO

Transcriptome analysis of memantine-treated Shank2 wild-type and knock-out mice

Project description:Shank2 is an excitatory postsynaptic scaffolding protein strongly implicated in autism spectrum disorders (ASD). Shank2-mutant mice with a homozygous deletion of exons 6 and 7 show decreased NMDA receptor (NMDAR) functions and autistic-like behaviors in juvenile (~postnatal day or P21) and adult (> P56) stages that are rescued by NMDAR activation. These mice, however, show an opposite change increased NMDAR functions—at ~P14, and NMDAR suppression by early and chronic memantine treatment during P7–21 prevents NMDAR hypofunction and autistic-like behaviors at juvenile (~P21) and adult (~P56) stages. To explore molecular mechanisms underlying the long-lasting effects of early memantine treatment, we performed RNA-Seq analysis of forebrains from wild-type and Shank2-mutant mice early and chronically treated with vehicle or memantine. Memantine-treated Shank2-mutant mice showed upregulations of chromatin-related genes and downregulations of mitochondria- and ribosome-related genes. In addition, vehicle-treated Shank2-mutant mice showed transcriptomic patterns that are largely opposite to those observed in ASD, as supported by the expression patterns of ASD-risk/related genes and cell-type-specific genes. These patterns, likely representing compensatory changes, were weakened by early memantine treatment. These results suggest that early chronic memantine treatment in Shank2-mutant mice alters chromatin- and mitochondria/ribosome-related gene expressions and weakens anti-ASD transcriptomic patterns.

2021-10-06 | GSE171931 | GEO

Abnormalities in Prefrontal Cortical Gene Expression Profiles Relevant to Schizophrenia in MK801-Exposed C57BL/6 Mice.

Project description:MK-801, a non-competitive NMDA receptor (NMDAR) antagonist, disturbs NMDAR function in rodents and induces psychological and behavioral changes similar to schizophrenia(SCZ). However, the effects of MK-801 treatment on gene expression in prefrontal cortex (PFC) are largely unknown. We have established MK-801 animal models to explore the etiology and pathophysiology of schizophrenia. Transcriptome analysis of the prefrontal cortex reveals that the differentially expressed genes mainly aggregate in chemical synaptic transmission and immune system process. Gene association patterns which are involved in synaptic vesicle cycle and mitochondrial electron transport chain have also been altered. Together, these observations underscore that dysfunction in glutamatergic synaptic vesicle cycle and mitochondrial electron transport chain has an impact on the pathogenesis of SCZ.

2019-03-12 | GSE111708 | GEO

Reduced CYFIP1 in human neural progenitors as 15q11.2 deletion model: donor specific dysregulation of schizophrenia/epilepsy genes

Project description:Deletions at 15q11.2 have been established to increase risk for multiple neurodevelopmental disorders (NDDs) including schizophrenia and epilepsy, yet show variable expressivity between individuals. To investigate the potential role of CYFIP1, a gene within the locus, we carried out knockdown experiments in human neural progenitor cells derived from 15q11.2 neutral induced pluripotent stem cells. Transcriptional profiling and cellular assays support a prominent role for CYFIP1 in cytoskeletal remodeling across all lines examined. Validating the utility of this model for study of disease, genes implicated in schizophrenia and epilepsy but not other disorders or traits unrelated to the deletion, were enriched among mRNAs dysregulated following knockdown. Importantly, and consistent with the variable expressivity of 15q11.2 deletions, the magnitude of disease-related effects varied between donor lines. Towards mechanisms, FMRP targets and synaptic genes were overrepresented among dysregulated mRNAs and as such may contribute to the schizophrenia and epilepsy effects we observe. Further model validation, and new candidate epilepsy genes, comes from machine-learning analyses showing a striking similarity between a subset of dysregulated transcripts and well-established epilepsy genes. Results provide support for an important contribution of CYFIP1 in 15q11.2 mediated risk for NDDs and demonstrate that disease-related biological signatures are evident prior to neuronal differentiation. This new human model of disease will be useful in identifying compounds that could ameliorate outcomes in deletion carriers.

2016-09-22 | GSE70935 | GEO

Transcriptomic signatures of risk genes implicated in psychiatric disorders during neuronal differentiation

Project description:Susceptibility genes for Autism Spectrum Disorder (ASD), Fragile X Syndrome (FXS), monogenetic disorders with intellectual disabilities (ID) or schizophrenia (SCZ) converge on processes related to neuronal function and differentiation. Furthermore, ASD risk genes are enriched for FMRP (Fragile X Mental Retardation Protein) targets and for genes implicated in ID. In addition, a significant co-heritability was observed between ASD and SCZ. The genetic overlap between ASD, FXS, ID and SCZ together with the symptomatic differences gives rise to the question if pathomechanisms impair the same or different regulatory patterns activated during neuronal differentiation (ND). To test this idea, we performed transcriptome analysis of in-vitro differentiation of the neuroblastoma cell line model SH-SY5Y and identified genes that were differentially expressed, dynamically regulated, and coordinately expressed. The identified genetic modules activated during ND are enriched for genetic risk factors for these four disorders. Although risk genes for the disorders significantly overlap, we observed disorder specific enrichments: ASD or FXS implicated genes were likely to be positive regulators of ND whereas ID implicated genes were related to negative regulation. ASD and SCZ genes were specifically enriched among cholesterol and fatty acid associated modules. ID genes were overrepresented among cell cycle modules. In addition, we show that ASD genes are likely to be hub genes. We hypothesize that knowledge about genetic variants of an individual combined with network and pathway context of the related genes will allow differentiating between psychiatric disorders. 21 samples, consisting of 3 replicates harvested at 7 different time-points of RA+BDNF-induced neuronal differentiation

2016-06-01 | E-GEOD-69838 | biostudies-arrayexpress

Translatome analysis in postmortem brain-derived samples from Autism Spectrum Disorder affected individuals

Project description:Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a strong genetic link, but no single well-established cause. This suggests that perturbed regulatory network may better explain its heterogeneity of phenotypes and multiple gene associations. Consistently, our previous study provided evidence of abnormal alternative polyadenylation in transcripts from distinct brain regions suggesting a potential imbalance in the protein synthesis in the postsynaptic density. To test this hypothesis, we studied transcriptome-wide alterations of mRNA translation in post-mortem brain samples from neurotypical and ASD-affected young males subjects. To this end, we employed an optimised polysome profiling technique amendable for small tissue samples and analyzed changes in the translatome using the anota2seq algorithm. The analysis revealed bolstered translation of mRNAs whose translational efficiency was previously reported to be sensitive to eIF4E, a key factor for synaptic protein synthesis modulated by Ras/ERK and PI3K/mTOR signaling pathways. This observation is consistent with previous findings linking hyperactive eIF4E to increased translation of neuroligins, a disturbed excitation/inhibition ratio in synapses and autistic-like phenotypes in mice. In summary, we reveal a link between eIF4E-dependent translation and human autism, indicating a potential pharmacy-therapeutical target for the prevention of behavioral impairments in ASD.

2023-10-27 | GSE236761 | GEO

Transcriptomic signatures of risk genes implicated in psychiatric disorders during neuronal differentiation

2016-06-01 | GSE69838 | GEO

Autophagic vesicle content profiling from hippocampal slices LC-MSMS

Project description:Previous work demonstrated that the developmental pruning of dendritic spines requires autophagy. This developmental process is facilitated by long-term depression (LTD)-like mechanisms, inviting the speculation that LTD, a fundamental form of plasticity, itself requires autophagy. Here, we show that LTD-inducing activation of NMDA receptors or metabotropic glutamate receptors triggers the rapid initiation of autophagy in postsynaptic dendrites. Dendritic autophagic vesicles (AVs) act in parallel with the endocytic machinery to remove AMPAR subunits from the surface and rapidly degrade them and their scaffold PSD95. Moreover, during NMDAR-LTD, key postsynaptic proteins are sequestered for autophagic degradation, as revealed by quantitative proteomic profiling of purified AVs. In turn, pharmacological inhibition of AV biogenesis, or conditional ablation of atg5 in pyramidal neurons abolishes LTD and instead triggers sustained potentiation in the hippocampus. These deficits in synaptic plasticity are recapitulated by knockdown of atg5 specifically in postsynaptic pyramidal neurons in the CA1 area. Conducive to the role of synaptic plasticity in behavioral flexibility, mice with autophagy deficiency in excitatory neurons exhibit altered response in reversal learning. Therefore, local assembly of the autophagic machinery in dendrites ensures the degradation of postsynaptic components and facilitates LTD expression.

2022-01-10 | PXD030079 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data