Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA322140 | ENA |
REPOSITORIES: ENA
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Project description:Synaptic dysfunction in human neurons with Autism associated deletions in PTCHD1-AS
| PRJNA532882 | ENA
Project description:The Xp22.11 locus that encompasses PTCHD1, DDX53, and the long noncoding RNA (lncRNA) PTCHD1-AS is frequently disrupted in males with autism spectrum disorder (ASD), but the functional consequences of these genetic risk factors for ASD are unknown. : iPSC-derived neurons from the ASD subjects exhibited reduced miniature excitatory post-synaptic current (mEPSC) frequency and NMDA receptor hypofunction. We found that 35 ASD-associated deletions mapping to the PTCHD1 locus disrupt exons of PTCHD1-AS. We also report a novel ASD-associated deletion of PTCHD1-AS exon 3, and we show exon 3 loss alters PTCHD1-AS splicing without affecting expression of the neighboring PTCHD1 coding gene. Finally, targeted disruption of PTCHD1-AS exon 3 recapitulated diminished mEPSC frequency, supporting a role for the lncRNA in the etiology of ASD. Our genetic findings provide strong evidence that PTCHD1-AS deletions are risk factors for ASD, and human iPSC-derived neurons implicate these deletions in the neurophysiology of excitatory synapses and in ASD-associated synaptic impairment.
2019-09-03 | GSE129808 | GEO
Project description:Heterozygous NRXN1 deletions constitute the most prevalent currently known single-gene mutation associated with schizophrenia, and predispose to multiple other neurodevelopmental disorders. Previous studies showed that engineered heterozygous NRXN1 deletions impaired neurotransmitter release in human neurons, suggesting a synaptic pathophysiological mechanism. Utilizing this observation for drug discovery, however, requires confidence in its robustness and validity. Here, we describe a multi-center effort to test the generality of this pivotal observation, using independent analyses at two laboratories of patient-derived and newly engineered human neurons with heterozygous NRXN1 deletions. We show that in neurons that were trans-differentiated from induced pluripotent stem cells derived from three NRXN1-deletion patients, the same impairment in neurotransmitter release was observed as in engineered NRXN1-deficient neurons. This impairment manifested as a decrease in spontaneous synaptic events and in evoked synaptic responses, and an alteration in synaptic paired-pulse depression. Nrxn1-deficient mouse neurons generated from embryonic stem cells by the same method as human neurons did not exhibit impaired neurotransmitter release, suggesting a human-specific phenotype. NRXN1 deletions produced a reproducible increase in the levels of CASK, an intracellular NRXN1-binding protein, and were associated with characteristic gene expression changes. Thus, heterozygous NRXN1 deletions robustly impair synaptic function in human neurons regardless of genetic background, enabling future drug discovery efforts.
2021-03-12 | GSE168762 | GEO
Project description:The autism-associated synaptic-adhesion gene Neuroligin-4 (NLGN4) is poorly conserved evolutionarily, limiting conclusions from Nlgn4 mouse models for human cells. Here, we show that the cellular and subcellular expression of human and murine Neuroligin-4 differ, with human Neuroligin-4 primarily expressed in cerebral cortex and localized to excitatory synapses. Overexpression of NLGN4 in human neurons resulted in an increase in excitatory synapse numbers but a remarkable decrease in synaptic strength. Human neurons carrying the syndromic autism mutation NLGN4-R704C also formed more excitatory synapses but with increased functional synaptic transmission due to a postsynaptic mechanism, while genetic loss of NLGN4 did not significantly affect synapses in the human neurons analyzed. Thus, the NLGN4-R704C mutation represents a change of function mutation. Our work reveals contrasting roles of NLGN4 in human and mouse neurons, suggesting human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.
2019-06-27 | GSE131428 | GEO
Project description:Synaptic dysfunction represents a key pathophysiology in neurodevelopmental disorders such as autism spectrum disorder (ASD). Rare mutation R451C in human Neuroligin 3 (NLGN3, encoded by X-linked gene NLGN3), a cell adhesion molecule essential for synapse formation, has been linked to ASD. Despite success in recapitulating the social interaction behavioral deficits and the underlying synaptic abnormalities in mouse model, the impact of NLGN3 R451C on the human neuronal system remains elusive. Here, we generated isogenic knock-in human pluripotent stem cell lines harboring NLGN3 R451C allele and examined its impact on synaptic transmission. Analysis of co-cultured excitatory and inhibitory induced neurons (iNs) with mutation revealed an augmentation in excitatory synaptic strength comparing to isogenic control, but not in inhibitory synaptic transmission. Consistently, the augmentation in excitatory transmission was confirmed in iNs transplanted into mouse forebrain. Using single-cell RNA seq on co-cultured excitatory and inhibitory iNs, we identified differential expression genes (DEGs) and found NLGN3 R451C alters gene networks associated with synaptic transmission. Gene ontology and enrichment analysis revealed convergent gene networks associated with ASD and other mental disorders. Our finding suggests that the NLGN3 R451C mutation could preferentially impact excitatory neurons, which causes overall network properties changes and excitation-inhibition imbalance related to mental disorders.
2022-10-26 | GSE180751 | GEO
Project description:The long non-coding (lnc) RNA PTCHD1-AS is frequently disrupted in males with autism spectrum disorder (ASD), but its role in neuron function is unknown. We generated induced pluripotent stem (iPS) cells from two ASD subjects with PTCHD1 locus microdeletions, and produced neurons that exhibited reduced miniature excitatory post-synaptic current (mEPSC) frequency and NMDA receptor hypofunction. Mutation of the lncRNA PTCHD1-AS had no impact on expression of the divergently transcribed neighboring PTCHD1 gene in cis, but 14 genes were differentially expressed. Alternative splicing patterns of the nuclear lncRNA were affected by exon 3 loss, and its importance was reinforced by discovery of a novel ASD-associated exon 3 deletion. Finally, genome editing of exon 3 in iPS cells recapitulated diminished mEPSC frequency in neurons. Our findings directly implicate PTCHD1-AS in excitatory synapse function, and reveal the first association of lncRNA deletion with neuronal under-connectivity in ASD.
2019-05-18 | GSE81624 | GEO
Project description:The roles of long noncoding RNAs (lncRNAs) in synaptic transmission and neuronal development are emerging. Here we applied an integrated bioinformatic/biological screening strategy to identify lncRNAs that regulate synaptic vesicle release. We identified neuroLNC, a conserved neuron-specific nuclear lncRNA that modulates synaptic vesicle release, presynaptic calcium influx, neurite elongation and neuronal migration. In neurons neuroLNC interacts with a neurodegeneration-associated protein and tunes a set of presynaptic transcripts implicated in neurotransmitter release.
2020-05-26 | PXD013434 | Pride
Project description:Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). To investigate their effect on synaptic connectivity, we generated cortical neurons from induced pluripotent stem cells (iPSC) derived from neurotypic and ASD-affected donors. We developed Sparse coculture for Connectivity (SparCon) assays where SHANK2 and control neurons were differentially labeled and sparsely seeded together on a lawn of unlabeled control neurons. We observed striking increases in total synapse number and dendrite complexity. Dendrite length increases were exacerbated by IGF1 or BDNF treatment. Increased excitatory synapse function in haploinsufficient SHANK2 neurons was phenocopied in gene-edited knockout SHANK2 neurons. Gene correction of an ASD SHANK2 mutation rescued excitatory synapse function supporting a role for SHANK2 as a negative regulator of connectivity in developing human neurons. The transcriptome in these isogenic SHANK2 neurons was deeply perturbed in synaptic and plasticity gene sets and ASD gene modules, and activity dependent dendrite extension was defective. Our unexpected findings provide evidence for hyperconnectivity and profoundly altered transcriptome in SHANK2 neurons derived from ASD subjects.
2019-02-04 | GSE122550 | GEO
Project description:Abnormalities in neocortical and synaptic development have been associated with neurodevelopmental disorders. However, the molecular and cellular mechanisms regulating the formation of the initial synapses in an evolutionary advanced neocortical layer, the subplate (SP), are poorly understood. Our snRNAseq screen of human prefrontal neocortices from early (11/12 PCW), mid (14/15 PCW) to late (17/18 PCW) fetal developmental stages revealed the bipartite-to-tripartite differentiation of SP neuronal subclasses. Using polysome profiling with RNAseq, we report for the first time a set of mRNAs undergoing translational control in cellular subclasses of developing human prefrontal neocortices, including SP neurons. By examining both mouse and human neocortex, we further found that an autism spectrum disorder (ASD)-risk gene and RNA binding protein CUGBP Elav-Like Family Member 4 (CELF4) is selectively expressed in the neurons of two synapse-enriched compartments, the SP and the marginal zone. Furthermore, CELF4 binds mRNA targets that are encoded by the synaptic genes associated with ASD and adverse neurodevelopmental outcomes; albeit in an evolutionarily advanced fashion between mouse and human synaptic mRNAs. The selective forebrain Celf4 deletion from developing mouse cortical neurons disrupts the balance of SP synapses in a gender-specific fashion. Taken together, our results underscore the importance of RNA binding proteins and mRNA translation in evolutionarily advanced synaptic development, as well as their possible contribution to gender specific protein synthesis and vulnerability.
2023-08-07 | GSE214532 | GEO