Modeling Synaptic Mechanisms of Autism-associated Neuroligin-3 R451C Mutation Using Human Neurons
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ABSTRACT:
PROVIDER: PRJNA749412 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15235726.fastq.gz | Fastqsanger.gz | |||
| SRR15235727.fastq.gz | Fastqsanger.gz | |||
| SRR15235728.fastq.gz | Fastqsanger.gz |
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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 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:Synapse formation is a dynamic process essential for neuronal circuit development and maturation. At the synaptic cleft, trans-synaptic protein-protein interactions constitute major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity and its dysregulation has been implicated in neurodevelopmental disorders including autism spectrum disorders. However, the molecular mechanisms underlying E-I balance remains to be elucidated. Here, we investigate Neuroligin (Nlgn) genes which encode a family of postsynaptic adhesion molecules that shape excitatory and inhibitory synaptic function. We identified that NLGN3 protein differentially regulates inhibitory synaptic transmission in a splice isoform-dependent manner in hippocampal CA1 synapses. Distinct subcellular localization patterns of NLGN3 isoforms contribute to the functional differences observed among splice variants. Finally, our single-cell sequencing analysis reveals that Nlgn1 and Nlgn3 are the major Nlgn genes and that Nlgn splice isoforms are highly diverse in CA1 pyramidal neurons.
2020-05-05 | GSE143295 | GEO
Project description:Neuroligin-4 (NL4) loss-of-function mutations are strongly associated with monogenic heritable abnormalities linked with Autism Spectrum Disorder (ASD). NL4 mutation in mice causes ASD related alterations in both synaptic and behavioral phenotypes. Since microglia closely regulate synaptic development and are implicated as key players in ASD development and progression, we here studied microglial properties in the NL4-knock-out (NL4-/-) mouse model. We show that loss of NL4 caused altered behavior and impaired hippocampal gamma oscillations predominantly in male mice. In parallel, microglial density, morphology, and response to injury specifically in the CA3 region of the hippocampus were altered in NL4-/- males only. A transcriptomic and proteomic analysis revealed strong sexual dimorphism on molecular alterations in microglia of NL4-/-. Together, these results indicate that loss of NL4 affects not only neuronal network activity and behavior, but also changes the phenotype of microglia in a sex by genotype interaction .
2021-10-09 | GSE185419 | GEO
Project description:Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons
| PRJNA543517 | ENA
Project description:Neuroligin-4 (NL4) loss-of-function mutations are strongly associated with monogenic heritable abnormalities linked with Autism Spectrum Disorder (ASD). NL4 mutation in mice causes ASD related alterations in both, the synaptic and behavioral phenotype. Since microglia closely regulate synaptic development and are implicated as key players in ASD development and progression, we here studied microglial properties in the NL4-/- mouse model. We show that loss of NL4 caused altered behavior and impaired hippocampal gamma oscillations predominantly in male mice. In parallel, microglial density, morphology, and response to injury specifically in the CA3 region of the hippocampus were altered in NL4-deficient males only. A transcriptomic and proteomic analysis revealed a strong impact of sexual dimorphism on molecular alterations in microglia of NL4-deficient compared to wildtype mice. Estrogen application in male NL4-/- animals partially restored the impaired social behavior and the altered microglial phenotype. Together, these results indicate that loss of NL4 affects not only neuronal network activity and behavior, but changes in addition the phenotype of microglia in a sex-specific manner that could be targeted by estrogen treatment.
2023-10-24 | PXD024325 | Pride
Project description:Neuroligin 3 Splice Isoforms Shape Mouse Hippocampal Inhibitory Synaptic Function
| PRJNA599927 | ENA
Project description:We examined whether a human neuronal culture system could be used to assess the transcriptional program involved in human neural differentiation and in modeling some of the molecular features of a neurodevelopmental disorder such as autism. Primary normal human neuronal progenitors differentiation for 0, 2, 4, or 8 weeks.
2011-06-01 | E-GEOD-28046 | biostudies-arrayexpress
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:We examined whether a human neuronal culture system could be used to assess the transcriptional program involved in human neural differentiation and in modeling some of the molecular features of a neurodevelopmental disorder such as autism.
2011-06-01 | GSE28046 | GEO