Neuroligin-4 Regulates Excitatory Synaptic Transmission in Human Neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA543517 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9289340_1.fastq.gz | Fastqsanger.gz | |||
| SRR9289340_2.fastq.gz | Fastqsanger.gz | |||
| SRR9289341_1.fastq.gz | Fastqsanger.gz | |||
| SRR9289341_2.fastq.gz | Fastqsanger.gz | |||
| SRR9289342_1.fastq.gz | Fastqsanger.gz |
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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: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:The paraventricular hypothalamus (PVH) is crucial for food intake control, yet the presynaptic mechanisms underlying PVH neurons remain unclear. Here, we show that RUVBL2 in the PVH is significantly reduced during energy deficit, and knockout (KO) of PVH RUVBL2 results in hyperphagic obesity in mice. RUVBL2-expressing neurons in the PVH (PVHRUVBL2) exert the anorexigenic effect by projecting to the arcuate hypothalamus, the dorsomedial hypothalamus, and the parabrachial complex. We further demonstrate that PVHRUVBL2 neurons form the synaptic connections with POMC and AgRP neurons in the ARC. PVH RUVBL2 KO impairs the excitatory synaptic transmission by reducing presynaptic boutons and synaptic vesicles near active zone. Finally, RUVBL2 overexpression in the PVH suppresses food intake and protects against diet induced obesity. Together, this study demonstrates an essential role for PVH RUVBL2 in food intake control, and suggests that modulation of synaptic plasticity could be an effective way to curb appetite and obesity.
2024-10-02 | GSE249791 | GEO
Project description:Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits
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Project description:Excitatory synapses occur mainly on dendritic spines, and spine density is usually correlated with the strength of excitatory synaptic transmission. We report that Nr4a1, an activity-inducible gene encoding a nuclear receptor, regulates the density and distribution of dendritic spines in CA1 pyramidal neurons. Nr4a1 overexpression resulted in elimination of the majority of spines; however, postsynaptic densities were preserved on dendritic shafts, and the strength of excitatory synaptic transmission was unaffected, showing that excitatory synapses can be dissociated from spines. mRNA expression profiling studies suggest that Nr4a1-mediated transcriptional regulation of the actin cytoskeleton contributes to this effect. Under conditions of chronically elevated activity, when Nr4a1 was induced, Nr4a1 knockdown increased the density of spines and PSDs specifically at the distal ends of dendrites. Thus, Nr4a1 is a key component of an activity-induced transcriptional program that regulates the density and distribution of spines and synapses. After 10 days in culture, dissociated mouse hippocampal neurons in 6-well plates were infected with lentivirus expressing either Flag-Nr4a1 or GFP and incubated for 6 days to allow for transgene expression. Total RNA was then isolated using RNeasy Plus kit (QIAGEN). Samples passing an mRNA quality check proceeded to quantitative analysis on Agilent-026655 4x44 Mouse Microarrays.
2016-01-13 | E-GEOD-76805 | biostudies-arrayexpress
Project description:Synaptic plasticity has been shown to participate in control of energy homeostasis.The paraventricular hypothalamus (PVH) is crucial for satiety control, though the underlying synaptic mechanisms remain unclear. Here, we show that RUVBL2 in the PVH is significantly reduced during energy deficit, and knockout (KO) of PVH RUVBL2 leads to hyperphagic obesity. We further show that KO of PVH RUVBL2 impairs the excitatory synaptic transmission by reducing presynaptic boutons and altering synaptic vesicle distribution. Chromatin immunoprecipitation-sequencing (ChlP-seq) data show that RUVBL2 binds to the promoters of numerous genes related to synaptic plasticity, in particular synaptic vesicle and neuron axonogenesis. Meanwhile, RNA-seq data show significant changes in the expression of some genes in these two pathways. Together, this study demonstrates an essential role for PVH RUVBL2 in food intake control, and suggests that modulating synaptic plasticity could be an effective way to curb appetite and obesity.
2024-10-02 | GSE252308 | 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 embryonic stem cell-derived 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 that human evolution has impacted even fundamental cell biological processes generally assumed to be highly conserved.
| S-EPMC6706319 | biostudies-literature
Project description:Paraventricular hypothalamic RUVBL2 neurons suppress appetite by enhancing excitatory synaptic transmission in distinct neurocircuits [RNA-seq]
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Project description:Loh KH, Stawski PS, Draycott AS, Udeshi ND, Lehrman EK, Wilton DK, Svinkina T, Deerinck TJ, Ellisman MH, Stevens B, Carr SA, Ting AY. Cell 2016 Excitatory synapses are connections between neurons that promote the propagation of action potentials while inhibitory synapses repress them. Normal brain function relies on the careful balance of these antagonistic connections, which occur via molecularly distinct synaptic clefts. Understanding how this is
achieved relies on knowledge of their protein compositions, yet the clefts remain uncharacterized because they cannot be isolated biochemically. Here, we mapped the proteomes of two of the most common excitatory and inhibitory synaptic clefts in living neurons, using a spatially restricted enzymatic tagging strategy. These proteomes reveal dozens of novel synaptic candidates, and assign numerous known synaptic proteins to a specific cleft type. The molecular differentiation of each cleft allowed us to identify Mdga2 as a specificity factor regulating the presynaptic neurotransmitter recruiting activity of Neuroligin-2 at inhibitory synapses.
2016-06-23 | MSV000079849 | MassIVE