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

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

OTHER RELATED OMICS DATASETS IN: GSE59288

PROVIDER: PRJNA254971 | ENA |

REPOSITORIES: ENA

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

Project description: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.

2016-08-12 | GSE59288 | GEO

Modeling the functional genomics of autism using human neurons.

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Rescue of oxytocin response and social behavior in a rodent model of autism

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.

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CHD8 haploinsufficiency alters the developmental trajectories of human excitatory and inhibitory neurons linking autism phenotypes with transient cellular defects

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