No abstract

microRNA-218 (miR-218) has been linked to several cognition related neurodegenerative and neuropsychiatric disorders. However, whether miR-218 plays a direct role in cognitive functions remains unknown. Here, using the miR-218 knockout (KO) mouse model and the sponge/overexpression approaches, we showed that miR-218-2 but not miR-218-1 could bidirectionally regulate the contextual and spatial memory in the mice. Furthermore, miR-218-2 deficiency induced deficits in the morphology and presynaptic neurotransmitter release in the hippocampus to impair the long term potentiation. Combining the RNA sequencing analysis and luciferase reporter assay, we identified complement component 3 (C3) as a main target gene of miR-218 in the hippocampus to regulate the presynaptic functions. Finally, we showed that restoring the C3 activity in the miR-218-2 KO mice could rescue the synaptic and learning deficits. Therefore, miR-218-2 played an important role in the cognitive functions of mice through C3, which can be a mechanism for the defective cognition of miR-218 related neuronal disorders.

One of the main drivers of autism spectrum disorder (ASD) are risk alleles within hundreds of genes, which may interact within shared biological processes through as-yet unclear mechanisms. Here we develop a high-throughput genome-editing-mediated approach to target 14 high-confidence ASD genes within the mouse brain for proximity-based proteomics of endogenous interactomes. The resulting interactomes are enriched for human genes dysregulated in the brain of ASD patients and reveal unexpected, but highly significant, interactions with other lower confidence ASD-risk gene products, positing new avenues to prioritize genetic risk. Importantly, the datasets are enriched for shared cellular functions and genetic interactions that may underlie the disorder. We test this notion by spatial proteomics and CRISPR-based regulation of expression in two ASD models, demonstrating new functional interactions that modulate mechanisms of their dysregulation. Together, our results reveal native protein-interaction networks in ASD, providing new inroads for understanding its cellular neurobiology.