Differential Regulation of UBE3A Expression Following Neuronal Activation
Melinda M Peters, Aurelie Joly-Amado, Kevin R Nash, and Edwin J Weebert
Published November 1, 2025
https://doi.org/10.65856/RDCC3439
KEYWORDS: UBE3A, Angelman syndrome, paternal allele, maternal deletion, hippocampus, synaptic plasticity,neuronal activation, imprinting, Western blot, mouse model.
ABSTRACT: Angelman syndrome (AS) results from loss of the maternally inherited UBE3A allele, a neuronally imprinted gene essential for synaptic plasticity. While the maternal allele is active, the paternal copy is typically silenced, limiting therapeutic strategies. Here, we investigated activity-dependent regulation of maternal and paternal Ube3a using a YFP knock-in reporter that permits allele-specific protein quantification. In hippocampal slices, high-frequency stimulation and potassium depolarization triggered biphasic increases in UBE3A protein, with rapid early peaks and delayed secondary surges. Use of an in vivo, associative fear conditioning model revealed region-specific and allele-specific dynamics: hippocampal paternal Ube3a showed robust induction within 1–6 hours, maternal Ube3a exhibited sustained late upregulation, and parietal cortex expression from both alleles rose transiently within minutes. Prefrontal cortex responses were delayed, peaking at 6 hours. These results demonstrate that neuronal activity drives dynamic, allele-specific modulation of UBE3A across distinct cortical–hippocampal networks. Notably, paternal Ube3a can be transiently unsilenced following behavioral stimulation, revealing an untapped mechanism of regulation. This work highlights the potential to harness experience-dependent pathways to restore paternal UBE3A expression in AS, informing strategies for therapeutic reactivation.