ASH1L haploinsufficiency results in autistic-like phenotypes in mice and links Eph receptor gene to autism spectrum disorder

• Published in: Neuron (Cambridge, Mass.) Mass.), 2022-04, Vol.110 (7), p.1156-1172.e9
• Main Authors: Yan, Yuze, Tian, Miaomiao, Li, Meng, Zhou, Gang, Chen, Qinan, Xu, Mingrui, Hu, Yi, Luo, Wenhan, Guo, Xiuxian, Zhang, Cheng, Xie, Hong, Wu, Qing-Feng, Xiong, Wei, Liu, Shiguo, Guan, Ji-Song
• Format: Article
• Language: English
• Subjects: Animals; Ash1l; autism spectrum disorder; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - metabolism; Autistic Disorder - genetics; Disease Models, Animal; DNA-Binding Proteins - genetics; epigenetics; Haploinsufficiency; Histone-Lysine N-Methyltransferase - genetics; in vivo imaging; Mice; Mice, Knockout; Phenotype; Receptor, EphA1; synapse; synapse pruning
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2021.12.035

ASD-associated genes are enriched for synaptic proteins and epigenetic regulators. How those chromatin modulators establish ASD traits have remained unknown. We find haploinsufficiency of Ash1l causally induces anxiety and autistic-like behavior, including repetitive behavior, and alters social behavior. Specific depletion of Ash1l in forebrain induces similar ASD-associated behavioral defects. While the learning ability remains intact, the discrimination ability of Ash1l mutant mice is reduced. Mechanistically, deletion of Ash1l in neurons induces excessive synapses due to the synapse pruning deficits, especially during the post-learning period. Dysregulation of synaptic genes is detected in Ash1l mutant brain. Specifically, Eph receptor A7 is downregulated in Ash1l+/− mice through accumulating EZH2-mediated H3K27me3 in its gene body. Importantly, increasing activation of EphA7 in Ash1l+/− mice by supplying its ligand, ephrin-A5, strongly promotes synapse pruning and rescues discrimination deficits. Our results suggest that Ash1l haploinsufficiency is a highly penetrant risk factor for ASD, resulting from synapse pruning deficits. [Display omitted] •Ash1l haploinsufficiency induces ASD-associated behavior and discrimination deficit•Ash1l deficit blocks activity-dependent synapse elimination•EphA7 is downregulated via EZH2-H3K27me3 inhibition in Ash1l+/− mice•Enhancing EphA7 activity rescues synapse pruning deficit and behavioral abnormality Yan et al. describe Ash1l as a crucial epigenetic factor regulating activity-dependent synapse elimination in brain via promoting EphA7 expression. While Ash1l haploinsufficiency is a highly penetrant risk factor for ASD with synapse pruning deficits, engaging EphA7 activity rescues cellular and behavioral deficits in mice.