Constantine-Paton Research Laboratory, Instituto de Ciencias Biomédicas, Facultad de Medicina y Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile.
Programa de Doctorado en Ciencias, Mención Neurociencia, Universidad de Valparaíso, Valparaíso, Chile.
Sci Rep. 2024 Sep 2;14(1):20416. doi: 10.1038/s41598-024-70728-5.
Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions.
自闭症谱系障碍（ASD）是一种复杂的神经发育障碍，其特征是社交沟通、重复行为和兴趣受限。表观遗传修饰作为基因表达的关键调节剂，在控制大脑功能和行为方面起着至关重要的作用。赖氨酸（K）特异性去甲基酶 6B（KDM6B）是一种应激诱导的 H3K27me3 去甲基酶，是 ASD 风险最高的基因之一，但 KDM6B 突变对神经元活动和行为功能的精确影响仍不清楚。在这里，我们展示了 KDM6B 镶嵌性脑敲除对不同自闭症样表型表现的影响，包括重复行为、社会互动和明显的认知缺陷。此外，KDM6B 镶嵌性敲除显示海马兴奋性突触传递异常，降低 NMDA 受体介导的突触传递和可塑性。了解表观遗传修饰和神经元功能之间的复杂相互作用可能为 ASD 的病理生理学提供新的见解，并可能为有针对性的治疗干预措施的发展提供信息。
