Synaptic dysfunction in human neurons with Autism associated deletions in PTCHD1-AS
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ABSTRACT:
PROVIDER: PRJNA532882 | ENA |
REPOSITORIES: ENA
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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: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: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.
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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
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Project description:Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity-dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively up-regulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons. Mice lacking the Eif4g1 microexon display social behavior, learning and memory deficits, as well as alterations in hippocampal synaptic plasticity. The eIF4G microexons appear to reduce synaptic protein synthesis by causing ribosome stalling, through a mechanism whereby they promote the coalescence of cytoplasmic granule components associated with translation repression, including the Fragile X mental retardation protein, FMRP. The results thus reveal an autism-disrupted mechanism by which alternative splicing specializes translation to control higher-order cognitive functioning.
2020-01-30 | GSE141599 | GEO
Project description:Microexons represent the most highly conserved class of alternative splicing, yet their functions are poorly understood. Here, we focus on closely related neuronal microexons overlapping prion-like domains in the translation initiation factors, eIF4G1 and eIF4G3, the splicing of which is activity-dependent and frequently disrupted in autism. CRISPR-Cas9 deletion of these microexons selectively up-regulates synaptic proteins that control neuronal activity and plasticity and further triggers a gene expression program mirroring that of activated neurons. Mice lacking the Eif4g1 microexon display social behavior, learning and memory deficits, as well as alterations in hippocampal synaptic plasticity. The eIF4G microexons appear to reduce synaptic protein synthesis by causing ribosome stalling, through a mechanism whereby they promote the coalescence of cytoplasmic granule components associated with translation repression, including the Fragile X mental retardation protein, FMRP. The results thus reveal an autism-disrupted mechanism by which alternative splicing specializes translation to control higher-order cognitive functioning.
2020-01-30 | GSE141594 | GEO
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:Autism-associated deletions of the lncRNA PTCHD1-AS result in synaptic dysfunction in human neurons
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Project description:Presenilin mutations that alter γ-secretase activity cause familial Alzheimer's disease (AD), whereas ApoE4, an apolipoprotein for cholesterol transport, predisposes to sporadic AD. Both sporadic and familial AD feature synaptic dysfunction. Whether γ-secretase is involved in cholesterol metabolism and whether such involvement impacts synaptic function remains unknown. Here, we show that in human neurons, chronic pharmacological or genetic suppression of γ-secretase increases synapse numbers but decreases synaptic transmission by lowering the presynaptic release probability without altering dendritic or axonal arborizations. In search of a mechanism underlying these synaptic impairments, we discovered that chronic γ-secretase suppression robustly decreases cholesterol levels in neurons but not in glia, which in turn stimulates neuron-specific cholesterol-synthesis gene expression. Suppression of cholesterol levels by HMG-CoA reductase inhibitors (statins) impaired synaptic function similar to γ-secretase inhibition. Thus, γ-secretase enables synaptic function by maintaining cholesterol levels, whereas the chronic suppression of γ-secretase impairs synapses by lowering cholesterol levels.
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