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Synaptic dysfunction in human neurons with Autism associated deletions in PTCHD1-AS

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE129808 | GEO | 2019/09/03

REPOSITORIES: GEO

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Autism-associated deletions of the lncRNA PTCHD1-AS result in synaptic dysfunction in human neurons

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

Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse.

Project description:Synapse development and neuronal activity represent fundamental processes for the establishment of cognitive function. Structural organization as well as signalling pathways from receptor stimulation to gene expression regulation are mediated by synaptic activity and misregulated in neurodevelopmental disorders such as autism spectrum disorder (ASD) and intellectual disability (ID). Deleterious mutations in the PTCHD1 (Patched domain containing 1) gene have been described in male patients with X-linked ID and/or ASD. The structure of PTCHD1 protein is similar to the Patched (PTCH1) receptor; however, the cellular mechanisms and pathways associated with PTCHD1 in the developing brain are poorly determined. Here we show that PTCHD1 displays a C-terminal PDZ-binding motif that binds to the postsynaptic proteins PSD95 and SAP102. We also report that PTCHD1 is unable to rescue the canonical sonic hedgehog (SHH) pathway in cells depleted of PTCH1, suggesting that both proteins are involved in distinct cellular signalling pathways. We find that Ptchd1 deficiency in male mice (Ptchd1-/y) induces global changes in synaptic gene expression, affects the expression of the immediate-early expression genes Egr1 and Npas4 and finally impairs excitatory synaptic structure and neuronal excitatory activity in the hippocampus, leading to cognitive dysfunction, motor disabilities and hyperactivity. Thus our results support that PTCHD1 deficiency induces a neurodevelopmental disorder causing excitatory synaptic dysfunction.

2017-04-14 | GSE80312 | GEO

Copy number variation data from iPS cells with PTCHD1-AS deletions

Project description:iPS cell lines were generated from a male with ASD (proband or prb) and his unaffected mother (control or ctrl). Both individuals carry X-linked 167kb microdeletions that disrupt both PTCHD1 and PTCHD1-AS. We found that cells PTCHD1/PTCHD1-AS-null cells tended to have abnormal karyotypes. Copy number variation analyses were performed to examine genomic stability in control and proband iPS cell lines.

2019-05-18 | GSE83089 | GEO

Synaptic dysfunction in human neurons with Autism associated deletions in PTCHD1-AS

Project description:Synaptic dysfunction in human neurons with Autism associated deletions in PTCHD1-AS

| PRJNA532882 | ENA

SHANK2 mutations associated with autism spectrum disorder cause hyperconnectivity of human neurons

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

Mus musculus

Project description:Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse.

| PRJNA318532 | ENA

Transcriptome analysis of Shank2-heterozygous and -homozygous mice in different brain regions

Project description:Shank2 is an abundant excitatory postsynaptic scaffolding protein implicated in neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability, developmental delay, and schizophrenia. Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-HM mice) show ASD-like behavioral deficits and altered synaptic functions, although little is known about how different brain regions contribute to Shank2-mutant phenotypes. Here we attempted transcriptomic analyses of the prefrontal cortex, hippocampus, and striatum in adult Shank2-heterozygous/HT and Shank2-homozygous/HM mice. The mutant cortex, hippocampus, and striatum displayed distinct sets of differentially expressed genes associated with neuronal and synaptic functions in a gene dosage-differential manner. Gene set enrichment analyses of cortical Shank2-HT transcripts revealed increased synaptic gene expression and transcriptomic changes that are opposite to those observed in ASD (reverse-ASD), whereas cortical Shank2-HM transcripts displayed decreased synaptic gene expression and ASD-like transcriptomic patterns. The hippocampal Shank2-HT transcripts displayed minimally altered synaptic gene expression and mixed ASD-like and reverse-ASD patterns, whereas the Shank2-HM-hippocampus showed increased synaptic gene expression and reverse-ASD patterns. The striatal Shank2-HT/HM transcriptomes were largely similar to the hippocampal transcriptomes, although the main changes were observed in cell-type-specific genes, unlike the hippocampal changes mainly involving ASD-related/risk genes. These results indicate that heterozygous and homozygous Shank2 deletions in mice lead to brain region- and gene dosage-differential transcriptomic changes.

2022-11-02 | GSE200439 | GEO

Disruption of Autism Spectrum Disorder-Susceptibility Genes Predominantly Reduces Functional Connectivity of Isogenic Human Neurons

Project description:Autism Spectrum Disorder (ASD) is phenotypically and genetically heterogeneous, but genomic analyses have identified candidate susceptibility genes. We present a CRISPR gene editing strategy to insert a protein tag and premature termination sites creating an induced pluripotent stem cell (iPSC) knockout resource for functional studies of 10 ASD-relevant genes (AFF2/FMR2, ANOS1, ASTN2, ATRX, CACNA1C, CHD8, DLGAP2, KCNQ2, SCN2A, TENM1). Neurogenin 2 (NEUROG2)-directed differentiation of iPSCs allowed production of cortical excitatory neurons, and mutant proteins were not detectable. Using both patch-clamp and multi-electrode array approaches, the electrophysiological deficits measured were distinct for different mutations. However, they culminated in a consistent reduction in synaptic activity, including reduced spontaneous excitatory post-synaptic current frequencies in AFF2/FMR2-, ASTN2-, ATRX-, KCNQ2- and SCN2A-null neurons. RNAseq revealed convergence of several neuronal networks. Despite ASD susceptibility genes belonging to different gene ontologies, isogenic stem cell resources can reveal common functional phenotypes, such as reduced functional connectivity.

2018-11-01 | GSE107878 | GEO

Modeling Synaptic Mechanisms of Autism-associated Neuroligin-3 R451C Mutation Using Human Neurons

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

Mice lacking Astn2 have ASD-like behaviors and altered cerebellar circuit properties

Project description:Astrotactin 2 (ASTN2) is a transmembrane neuronal protein highly expressed in the cerebellum that functions in receptor trafficking and modulates cerebellar Purkinje cell (PC) synaptic activity. Individuals with ASTN2 mutations exhibit neurodevelopmental disorders, including autism spectrum disorder (ASD), ADHD, learning difficulties and language delay. To provide a genetic model for the role of the cerebellum in ASD-related behaviors and study the role of ASTN2 in cerebellar circuit function, we generated global and PC-specific conditional Astn2 knockout (KO and cKO, respectively) mouse lines. Astn2 KO mice exhibited strong ASD-related behavioral phenotypes, including a marked decrease in separation-induced pup ultrasonic vocalization calls, hyperactivity, and repetitive behaviors, altered behavior in the three-chamber test, and impaired cerebellar-dependent eyeblink conditioning. Hyperactivity and repetitive behaviors were also prominent in Astn2 cKO animals but they did not show altered behavior in the three-chamber test. By Golgi staining, Astn2 KO PCs had region-specific changes in dendritic spine density and filopodia numbers. Proteomic analysis of Astn2 KO cerebellum revealed a marked upregulation of ASTN2 family member, ASTN1, a neuron-glial adhesion protein. Immunohistochemistry and electron microscopy demonstrated a significant increase in Bergmann glia volume in the molecular layer of Astn2 KO animals. Electrophysiological experiments indicated a reduced frequency of spontaneous excitatory postsynaptic currents (EPSCs), as well as increased amplitudes of both spontaneous EPSCs and inhibitory postsynaptic currents (IPSCs) in the Astn2 KO animals, suggesting that pre- and postsynaptic components of synaptic transmission were altered. Thus, ASTN2 regulates ASD-like behaviors and cerebellar circuit properties.

2024-07-30 | PXD052868 | Pride

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