The Hippocampal Response to Acute Corticosterone Elevation Is Altered in a Mouse Model for Angelman Syndrome

Abstract

Angelman Syndrome (AS) is a severe neurodevelopmental disorder, caused by the neuronal absence of the ubiquitin protein ligase E3A (UBE3A). UBE3A promotes ubiquitin-mediated protein degradation and functions as a transcriptional coregulator of nuclear hormone receptors, including the glucocorticoid receptor (GR). Previous studies showed anxiety-like behavior and hippocampal-dependent memory disturbances in AS mouse models. Hippocampal GR is an important regulator of the stress response and memory formation, and we therefore investigated whether the absence of UBE3A in AS mice disrupted GR signaling in the hippocampus. We first established a strong cortisol-dependent interaction between the GR ligand binding domain and a UBE3A nuclear receptor box in a high-throughput interaction screen. In vivo, we found that UBE3A-deficient AS mice displayed significantly more variation in circulating corticosterone levels throughout the day compared to wildtypes (WT), with low to undetectable levels of corticosterone at the trough of the circadian cycle. Additionally, we observed an enhanced transcriptomic response in the AS hippocampus following acute corticosterone treatment. Surprisingly, chronic corticosterone treatment showed less contrast between AS and WT mice in the hippocampus and liver transcriptomic responses. This suggests that UBE3A limits the acute stimulation of GR signaling, likely as a member of the GR transcriptional complex. Altogether, these data indicate that AS mice are more sensitive to acute glucocorticoid exposure in the brain compared to WT mice. This suggests that stress responsiveness is altered in AS which could lead to anxiety symptoms.

Hyperphagia, Growth, and Puberty in Children with Angelman Syndrome

“…UBE3A has been shown to be involved in nuclear hormone receptor functioning in the mouse brain [ 27 ]. This was especially noted in relation with the responsiveness to acute changes in corticosteroid levels.…”

Bone health in children with Angelman Syndrome at the ENCORE Expertise Center

“…Furthermore, it is remarkable that BHI-SDS is already lower than normal at a young age in all children with ASA role for UBE3A gene dysfunction with effect on nuclear hormone receptor function and possible effect on vitamin D and hormone function related to bone turnover has been suggested [10]. A recent mouse model study con rmed that UBE3A is involved in the nuclear hormone receptor function and cholesterol synthesis [31] (64). Another mouse model study reports on NIPA2 positively regulating osteogenic capacity of osteoblasts [32].…”

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder

“…As far as emotional problems are concerned, maternal Ube3a -deficient mice are under chronic stress and exhibit anxiety-like behaviors. Within the hippocampus, these mice demonstrate susceptibility to glucocorticoid exposure ( 127 ), disrupted glucocorticoid receptor signaling ( 127 – 129 ), and reduced number of parvalbumin-positive inhibitory interneurons ( 128 , 129 ), resulting in chronic stress, hippocampal hyperactivity and ultimately increased anxiety.…”