Dysregulation of neuronal activity-dependent immediate early genes in a mouse model of Angelman syndrome

Summary Angelman syndrome (AS) is a debilitating neurodevelopmental disorder triggered by impaired function of the maternal UBE3A gene, which codes a protein that functions as a ubiquitin ligase and transcriptional coactivator. Ube3a maternal deficient mice replicate many key behavioral deficits associated with AS; however, the underlying molecular mechanisms remain poorly understood. Using an RT 2 Profiler PCR array that summarizes the expression of 84 genes regulating synaptic plasticity, we identified a number of dysregulated genes in the visual cortex of AS mice brains at postnatal day 25 (P25) compared to wild-type animals. In-depth analysis revealed that various immediate early genes (IEGs), like Arc, Egr1-4, and Homer, are dramatically down-regulated in the visual cortex of AS mice with regard to wild-type controls at P25. Moreover, the dark rearing of wild-type mice considerably decreased the levels of these IEGs to nearly the same level as those found in AS mice, along with the down-regulation of Ube3a. Furthermore, a significant reduction in the expression of these IEGs can also be observed in the hippocampus of AS mice. Finally, we demonstrate that the augmented activity of HDAC2 in the AS mice brain might be connected with the down-regulation of various IEGs and other synaptic plasticity-regulating genes. These findings indicate that the deregulated expression of neural activity-dependent IEGs could be linked with abnormal synaptic plasticity and associated behavioral deficits observed in AS mice.