College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California 91766, USA.
College of Dental Medicine, Western University of Health Sciences, Pomona, California 91766, USA.
Neural Plast. 2022 Oct 4;2022:3923384. doi: 10.1155/2022/3923384. eCollection 2022.
Angelman syndrome (AS) is a rare neurodevelopmental disorder characterized by severe developmental delay, motor impairment, language and cognition deficits, and often with increased seizure activity. AS is caused by deficiency of UBE3A, which is both an E3 ligase and a cofactor for transcriptional regulation. We previously showed that the small conductance potassium channel protein SK2 is a UBE3A substrate, and that increased synaptic SK2 levels contribute to impairments in synaptic plasticity and fear-conditioning memory, as inhibition of SK2 channels significantly improved both synaptic plasticity and fear memory in male AS mice. In the present study, we investigated UBE3a-mediated regulation of synaptic plasticity and fear-conditioning in female AS mice. Results from both western blot and immunofluorescence analyses showed that synaptic SK2 levels were significantly increased in hippocampus of female AS mice, as compared to wild-type (WT) littermates. Like in male AS mice, long-term potentiation (LTP) was significantly reduced while long-term depression (LTD) was enhanced at hippocampal CA3-CA1 synapses of female AS mice, as compared to female WT mice. Both alterations were significantly reduced by treatment with the SK2 inhibitor, apamin. The shunting effect of SK2 channels on NMDA receptor was significantly larger in female AS mice as compared to female WT mice. Female AS mice also showed impairment in both contextual and tone memory recall, and this impairment was significantly reduced by apamin treatment. Our results indicate that like male AS mice, female AS mice showed significant impairment in both synaptic plasticity and fear-conditioning memory due to increased levels of synaptic SK2 channels. Any therapeutic strategy to reduce SK2-mediated inhibition of NMDAR should be beneficial to both male and female patients.
天使综合征（AS）是一种罕见的神经发育障碍，其特征是严重的发育迟缓、运动障碍、语言和认知缺陷，通常伴有癫痫活动增加。AS 是由 UBE3A 缺乏引起的，UBE3A 既是一种 E3 连接酶，也是转录调节的辅助因子。我们之前表明，小电导钾通道蛋白 SK2 是 UBE3A 的底物，而突触 SK2 水平的增加导致突触可塑性和恐惧条件记忆受损，因为抑制 SK2 通道可显著改善雄性 AS 小鼠的突触可塑性和恐惧记忆。在本研究中，我们研究了 UBE3a 介导的雌性 AS 小鼠突触可塑性和恐惧条件的调节。Western blot 和免疫荧光分析的结果表明，与野生型（WT）同窝仔相比，雌性 AS 小鼠海马中的突触 SK2 水平显著增加。与雄性 AS 小鼠一样，雌性 AS 小鼠海马 CA3-CA1 突触的长时程增强（LTP）显著降低，而长时程抑制（LTD）增强，与雌性 WT 小鼠相比。SK2 抑制剂 apamin 处理可显著降低这两种改变。与雌性 WT 小鼠相比，雌性 AS 小鼠 SK2 通道对 NMDA 受体的分流效应明显更大。雌性 AS 小鼠还表现出对上下文和音调记忆回忆的损害，apamin 治疗可显著减轻这种损害。我们的结果表明，与雄性 AS 小鼠一样，雌性 AS 小鼠由于突触 SK2 通道水平升高而导致突触可塑性和恐惧条件记忆明显受损。任何减少 SK2 介导的 NMDA 受体抑制的治疗策略都应该对男性和女性患者都有益。
