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Disruption of human-specific synaptogenesis program in autism [RNA-seq]

ABSTRACT: To test the connection between the molecular mechanisms underlying autistic disorder and human cognitive evolution, we analyzed the gene expression changes taking place during prefrontal cortex development in autism patients and healthy controls, as well as non-human primates. We found the genes with expression changes in autism are significantly overlapped with genes showing human-specific developmental profile. A major pattern of the overlapped genes reflects the aberrant acceleration of synaptogenesis and synaptic maturation followed by premature synaptic pruning in the prefrontal cortex of autism patients. This pattern involves the same developmental program that controls human-specific extension of cortical synaptogenesis in healthy individuals. Taken together, these findings shed light on the molecular mechanisms underlying autistic phenotype and provide potential targets for clinical intervention.

OTHER RELATED OMICS DATASETS IN: PRJNA254971

ORGANISM(S): Homo sapiens Pan troglodytes

PROVIDER: GSE59288 | GEO | 2016/08/12

SECONDARY ACCESSION(S): PRJNA254971

REPOSITORIES: GEO

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Amelioration of autism-like social deficits by targeting histone methyltransferases EHMT1/2 in Shank3-deficient mice

Project description:Many of the genes disrupted in autism are identified as histone-modifying enzymes and chromatin remodelers, most prominently those that mediate histone methylation/demethylation. However, the role of histone methylation enzymes in the pathophysiology and treatment of autism remains unknown. To address this, we used mouse models of haploinsufficiency of the Shank3 gene (a highly penetrant monogenic autism risk factor), which exhibits prominent autism-like social deficits. We found that histone methyltransferases EHMT1 and EHMT2, as well as histone lysine 9 dimethylation (specifically catalyzed by EHMT1/2), were selectively increased in the prefrontal cortex (PFC) of Shank3-deficient mice and autistic human postmortem brains. Treatment with the EHMT1/2 inhibitor UNC0642 or knockdown of EHMT1/2 in PFC induced a robust rescue of autism-like social deficits in Shank3-deficient mice, and restored NMDAR-mediated synaptic function. Activityregulated cytoskeleton-associated protein (Arc) was identified as one of the causal factors underlying the rescuing effects of UNC0642 on NMDAR function and social behaviors in Shank3-deficient mice. UNC0642 treatment also restored a large set of genes involved in neural signaling in PFC of Shank3-deficient mice. These results suggest that targeting histone methylation enzymes to adjust gene expression and ameliorate synaptic defects could be a potential therapeutic strategy for autism.

2020-07-29 | GSE155291 | GEO

Disruption of human-specific synaptogenesis program in autism [RNA-seq]

Project description:Disruption of human-specific synaptogenesis program in autism [RNA-seq]

| PRJNA254971 | ENA

Dosage-dependent differential transcriptomic changes in the prefrontal cortex of heterozygous and homozygous Shank2-mutant mice

Project description:Shank2 is an abundant postsynaptic scaffolding protein known to regulate excitatory synaptic assembly and function and is implicated in autism spectrum disorders (ASD). Whereas patient Shank2 mutations in autistic individuals are heterozygous, Shank2 functions studied in mice have mainly relied on the results from homozygous mutant mice, largely because of relatively strong synaptic and behavioral phenotypes. Moreover, although synaptic changes at juvenile and adult Shank2-mutant mice seem to be largely similar, it remains unclear whether there are any age-dependent changes across these stages at the molecular level. To address these questions, we attempted RNA-Seq analyses of the transcriptomes in the prefrontal cortex of both heterozygous and homozygous Shank2-mutant mice lacking exons 6 and 7 at juvenile and adult stages. The results indicate that heterozygous, but not homozygous, juvenile Shank2-mutant mice show strong transcriptomic changes that promote excitatory synaptic transmission and suppress ASD-related gene expressions. In contrast, adult Shank2-mutant mice show largely similar and dosage-dependent transcriptomic changes.

2021-05-27 | GSE168211 | GEO

Aberrant expression of lncRNAs in autistic brain

Project description:To assess for the potential contribution of dysregulated long non-coding RNA expression in autism pathogenesis, we profiled lncRNAs and mRNAs from post mortem brain tissue from autism patients and age/sex matched controls 4 brain tissue samples from autism patients (2 patients, 1 prefrontal cortex and cerebellum sample from each) were compared to 4 brain tissue samples from non-affected controls (2 patients, 1 prefrontal cortex and cerebellum sample from each)

2012-09-10 | E-GEOD-36315 | biostudies-arrayexpress

Meta-Analysis of Autism Cortical Transcriptome Reveals Discordant Region-Specific Changes Linked to Radial Glia and Inhibitory Interneurons

Project description:DNA methylation analysis of the prefrontal cortex samples from autistic patients and neurologically normal controls

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Striatum transcriptome analysis of Shank3 knock-out/heterozygous mice

Project description:Shank3 is a core excitatory postsynaptic protein expressed in multiple brain regions including the medial prefrontal cortex, striatum, and hippocampus. Shank3 knock-out mice display autism-like behaviors and synaptic dysfunction. To understand molecular mechanisms underlying the behavioral and synaptic changes, we performed transcriptome (RNA-sequencing) analysis of the striatum tissues from 10 to 12-week-old wild-type and Shank3 knock-out/heterozygous mice.

2019-09-11 | GSE124946 | GEO

Transcription profiling of mouse prefrontal cortex (ctrl vs transgenic synaptic AChE)

Project description:total prefrontal cortex RNA in female FVB/N mice (control) versus transgenic female mice overexpressing the human synaptic AChE

2008-06-16 | E-GEOD-937 | biostudies-arrayexpress

Hippocampus transcriptome analysis of CHD8 Asn2373LysfsX2 heterozygote mutation mice age of P25

Project description:CHD8, encoding a chromatin remodeling protein, is one of the most frequently mutated genes in autism spectrum disorders. However, how such mutations cause autistic behaviors remain unclear. In mice carrying a heterozygous frame-shift mutation in the Chd8 gene (Asn2373LysfsX2) identified in autistic human individuals, we observed autistic-like behaviors that are much stronger in males than in females, similar to human cases. These behaviors included enhanced mother-seeking ultrasonic vocalizations in pups, mother-attachment behaviors in juveniles, and isolation-induced self-grooming in adults. These behaviors were associated with opposite changes in synaptic excitation/inhibition and neuronal firing in male and female mice, but with strong changes in gene expression in female mice. Therefore, this CHD8 mutation may cause male-preponderant autistic-like behaviors in mice through differential synaptic/neuronal changes and gene expression

2018-06-15 | GSE103377 | GEO

Comparison of DEG between neonatal male and female mice age of P25 by CHD8 Asn2373LysfsX2 heterozygote mutation.

2018-06-15 | GSE87367 | GEO

Transcription profiling of mouse GAP-43 HZ and knockout mouse barrel cortex show modifications in genes associated with synaptogenesis and barrel map formation

Project description:Mice lacking the growth associated protein, GAP-43, (KO) show multiple deficits in forebrain axon guidance and cortical cell differentiation (Donovan and McCasland, 2005). As a result, GAP-43 KO mice fail to form barrels in mouse somatosensory cortex (S1) (Maier et al., 1999). GAP-43 heterozygous (HZ) mice show abnormalities in axonal pathfinding and show larger than normal barrels in layer IV S1 due to widely branched thalamocortical afferents (TCAs). Regardless of abnormalities during early development, HZ barrels become indistinguishable from WT by postnatal day 26. One explanation for these findings is that compensatory mechanisms may be activated in GAP-43 HZ cortex. We have used mRNA microarray expression analysis to gain a more comprehensive view of genes involved in GAP-43 signaling during barrel map formation. Using laser microdissection , cortical cells of the barrel cortex were excised, RNA extracted and used in GeneChip analysis. Expression profiling and functional gene group analysis of RNA from WT, HZ, and KO cortex at postnatal day 5 was performed. We identified thousands of transcripts differentially expressed across the genotypes. Verification of selected changes in gene expression was accomplished using in situ hybridization. Our results suggest an adaptive modification in transcript expression of genes involved in cell-cell communication and synaptogenesis. These modifications appear important in forward and reverse signaling as well as maintaining synchrony between the cells. Compensatory up- and down regulation of synapse-associated genes may explain the reverse in HZ phenotype from P7 to P26. Moreover, these findings provide new insight into the role GAP-43 plays in several pathways associated with synaptogenesis and trans-synaptic signaling. Experiment Overall Design: 3 replicate RNA samples were prepared from laser microdissected barrel cortex samples of WT, HZ and KO mice at a single timepoint (postnatal day 5)

2009-06-08 | E-GEOD-12687 | biostudies-arrayexpress

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