Ringelberg Nicholas W, Mayfield Renée E, Lord Julia S, Diering Graham H, Burette Alain C, Philpot Benjamin D
Neuroscience Curriculum, University of North Carolina, Chapel Hill, 27599-7255.
Neuroscience Center, University of North Carolina, Chapel Hill, 27599-7255.
eNeuro. 2025 Sep 11. doi: 10.1523/ENEURO.0453-24.2025.
Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by loss of expression of the maternal allele, and is characterized by a constellation of impactful neurological symptoms. While previous work has uncovered outsized contributions of GABAergic neuron-selective deletion to seizure susceptibility and electroencephalography (EEG) phenotypes in a mouse model of AS, the neuronal populations governing a broader range of behaviors have not been studied. Here, we used male and female mice to test the consequences of deletion from GABAergic or glutamatergic neurons across a well-characterized battery of AS-relevant behaviors. Surprisingly, we observed deficits in numerous motor and innate behaviors in mice with glutamatergic deletion, and relatively few consequences of GABAergic deletion. Furthermore, genetic reinstatement in glutamatergic neurons rescued multiple motor and innate behaviors. When tested for sleep-wake behaviors, the selective loss of from glutamatergic neurons disrupted sleep similarly to that of AS model mice ( ), and glutamatergic reinstatement overcame the lack of active cycle "siesta" and decreased REM phenotypes observed in AS model mice. Altogether, this work demonstrates a major role of glutamatergic neuron UBE3A loss in mediating multiple AS behavioral features, suggesting a divergence from the circuitry underlying enhanced seizure susceptibility. Our findings imply that neuronal cell type agnostic UBE3A reinstatement is likely required for successful AS genetic therapies-with reinstatement of UBE3A in GABAergic neurons necessary for overcoming epileptic and EEG phenotypes, and reinstatement in glutamatergic neurons necessary for overcoming most other behavioral phenotypes. Angelman syndrome (AS), a severe neurodevelopmental disorder caused by loss of neuronal UBE3A, is characterized by symptoms such as motor impairment, lack of speech, seizures, and disrupted sleep. While clinical trials aim to restore UBE3A in AS individuals, the neuronal populations responsible for key symptoms remain unclear. Using an AS mouse model, we identify a key role for excitatory neuron loss of UBE3A in motor, innate behavior, and sleep phenotypes, distinct from the previously described impact of inhibitory neuron loss of UBE3A on seizure and electroencephalography phenotypes. These data improve our understanding of the mechanisms by which UBE3A loss leads to symptoms, potentially guiding future therapies.
天使综合征（Angelman syndrome，AS）是一种罕见的神经发育障碍，由母本等位基因表达缺失引起，其特征为一系列严重的神经症状。虽然先前的研究发现，在天使综合征小鼠模型中，GABA能神经元选择性缺失对癫痫易感性和脑电图（EEG）表型有显著影响，但尚未对控制更广泛行为的神经元群体进行研究。在此，我们使用雄性和雌性小鼠，通过一系列特征明确的与天使综合征相关的行为测试，来探究GABA能或谷氨酸能神经元中UBE3A缺失的后果。令人惊讶的是，我们发现谷氨酸能UBE3A缺失的小鼠在多种运动和先天行为方面存在缺陷，而GABA能UBE3A缺失的影响相对较小。此外，在谷氨酸能神经元中恢复UBE3A可挽救多种运动和先天行为。在测试睡眠-觉醒行为时，谷氨酸能神经元中UBE3A的选择性缺失对睡眠的干扰与天使综合征模型小鼠相似，而恢复谷氨酸能UBE3A可克服天使综合征模型小鼠中观察到的主动周期“午睡”缺失和快速眼动睡眠表型减少的问题。总之，这项研究表明谷氨酸能神经元UBE3A缺失在介导天使综合征的多种行为特征中起主要作用，这表明其与癫痫易感性增强背后的神经回路存在差异。我们的研究结果表明，成功的天使综合征基因治疗可能需要在不考虑神经元细胞类型的情况下恢复UBE3A，其中在GABA能神经元中恢复UBE3A对于克服癫痫和EEG表型是必要的，而在谷氨酸能神经元中恢复UBE3A对于克服大多数其他行为表型是必要的。天使综合征（AS）是一种由神经元UBE3A缺失引起的严重神经发育障碍，其特征包括运动障碍、语言缺失、癫痫发作和睡眠紊乱等症状。虽然临床试验旨在恢复天使综合征患者体内的UBE3A，但导致关键症状的神经元群体仍不清楚。利用天使综合征小鼠模型，我们确定了兴奋性神经元UBE3A缺失在运动、先天行为和睡眠表型中的关键作用，这与先前描述的抑制性神经元UBE3A缺失对癫痫发作和脑电图表型的影响不同。这些数据增进了我们对UBE3A缺失导致症状的机制的理解，可能为未来的治疗提供指导。
