Defective glucocorticoid hormone receptor signaling leads to increased stress and anxiety in a mouse model of Angelman syndrome

• Published in: Human molecular genetics 2012-04, Vol.21 (8), p.1824-1834
• Main Authors: GODAVARTHI, Swetha K, DEY, Parthanarayan, MAHESHWARI, Megha, JANA, Nihar Ranjan
• Format: Article
• Language: English
• Subjects: Amygdala - metabolism; Angelman Syndrome - metabolism; Angelman Syndrome - pathology; Angelman Syndrome - psychology; Animal models; Animals; Anxiety; Anxiety - etiology; Biological and medical sciences; Blood; Brain - metabolism; Cell receptors; Cell structures and functions; Corticosterone; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; GABAergic Neurons - chemistry; GABAergic Neurons - physiology; Genetics of eukaryotes. Biological and molecular evolution; Glucocorticoid receptors; Glucocorticoids; Hippocampus; Hippocampus - pathology; Hormone receptors. Growth factor receptors. Cytokine receptors. Prostaglandin receptors; Immediate-Early Proteins - metabolism; Interneurons; Interneurons - chemistry; Interneurons - physiology; Malformations of the nervous system; Medical sciences; Mice; Molecular and cellular biology; Mutation; Neurodevelopmental disorders; Neurology; Parvalbumins - analysis; Protein-Serine-Threonine Kinases - metabolism; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Signal Transduction; Steroid hormone receptors; Stress; Stress, Psychological - etiology; Transcription; Transcriptional Activation; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddr614

Angelman syndrome (AS) is a neurodevelopmental disorder caused due to deletions or loss-of-function mutations in maternally inherited UBE3A. Ube3a functions as an ubiquitin ligase as well as a transcriptional coactivator of steroid hormone receptors. However, the mechanisms by which maternal Ube3a deficiency gives rise to phenotypic features of AS are not clear. We report here that Ube3a regulates glucocorticoid receptor (GR) transactivation and GR signaling pathway is disrupted in Ube3a-maternal-deficient mice brain. The expression of several GR-dependent genes is down-regulated in multiple brain regions of Ube3a-maternal-deficient mice. AS mice show significantly higher level of blood corticosterone, selective loss of GR and reduced number of parvalbumin-positive inhibitory interneurons in their hippocampus that could ultimately lead to increased stress. These mice also exhibit increased anxiety-like behavior, which could be due to chronic stress. Altogether, our findings suggest that chronic stress due to altered GR signaling might lead to anxiety-like behavior in a mouse of model of AS.