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1.
bioRxiv ; 2024 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-39229156

RESUMO

Over a hundred risk genes underlie risk for autism spectrum disorder (ASD) but the extent to which they converge on shared downstream targets to increase ASD risk is unknown. To test the hypothesis that cellular context impacts the nature of convergence, here we apply a pooled CRISPR approach to target 29 ASD loss-of-function genes in human induced pluripotent stem cell (hiPSC)-derived neural progenitor cells, glutamatergic neurons, and GABAergic neurons. Two distinct approaches (gene-level and network-level analyses) demonstrate that convergence is greatest in mature glutamatergic neurons. Convergent effects are dynamic, varying in strength, composition, and biological role between cell types, increasing with functional similarity of the ASD genes examined, and driven by cell-type-specific gene co-expression patterns. Stratification of ASD genes yield targeted drug predictions capable of reversing gene-specific convergent signatures in human cells and ASD-related behaviors in zebrafish. Altogether, convergent networks downstream of ASD risk genes represent novel points of individualized therapeutic intervention.

2.
Cell Rep ; 42(3): 112243, 2023 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-36933215

RESUMO

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Animais , Transtorno Autístico/genética , Peixe-Zebra/genética , Encéfalo , Transtorno do Espectro Autista/genética , Mapeamento Encefálico
3.
Brain Behav ; 11(4): e02041, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33484493

RESUMO

BACKGROUND: Autism spectrum disorder (ASD) and epilepsy are highly comorbid, suggesting potential overlap in genetic etiology, pathophysiology, and neurodevelopmental abnormalities; however, the nature of this relationship remains unclear. This work investigated how two ion channel mutations, one associated with autism (Scn2a-null) and one with epilepsy (Kcna1-null), interact to modify genotype-phenotype relationships in the context of autism. Previous studies have shown that Scn2a+/- ameliorates epilepsy in Kcna1-/- mice, improving survival, seizure characteristics, and brain-heart dynamics. Here, we tested the converse, whether Kcna1 deletion modifies ASD-like repetitive and social behaviors in Scn2a+/- mice. METHODS: Mice were bred with various combinations of Kcna1 and Scn2a knockout alleles. Animals were assessed for repetitive behaviors using marble burying, grooming, and nestlet shredding tests and for social behaviors using sociability and social novelty preference tests. RESULTS: Behavioral testing revealed drastic reductions in all repetitive behaviors in epileptic Kcna1-/- mice, but relatively normal social interactions. In contrast, mice with partial Kcna1 deletion (Kcna1+/- ) exhibited increased self-grooming and decreased sociability suggestive of ASD-like features similar to those observed in Scn2a+/- mice. In double-mutant Scn2a+/- ; Kcna1+/- mice, the two mutations interacted to partially normalize ASD-like behaviors associated with each mutation independently. CONCLUSIONS: Taken together, these findings suggest that Kv1.1 subunits are important in pathways and neural networks underlying ASD and that Kcna1 may be a therapeutic target for treatment of Scn2a-associated ASD.


Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Animais , Transtorno do Espectro Autista/genética , Modelos Animais de Doenças , Asseio Animal , Haploinsuficiência , Canal de Potássio Kv1.1 , Camundongos , Camundongos Knockout , Comportamento Social
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