Defective glucocorticoid hormone receptor signaling leads to increased stress and anxiety in a mouse model of Angelman syndrome.
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.
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122 050, India.
Swetha K
SK
Godavarthi
Parthanarayan
P
Dey
Megha
M
Maheshwari
Nihar Ranjan
NR
Jana
D000679:Amygdala / Q000378:metabolism; D017204:Angelman Syndrome / Q000378:metabolism* / Q000473:pathology / Q000523:psychology*; D000818:Animals; D001007:Anxiety / Q000209:etiology*; D001921:Brain / Q000378:metabolism*; D004195:Disease Models, Animal; D059330:GABAergic Neurons / Q000737:chemistry / Q000502:physiology; D006624:Hippocampus / Q000473:pathology; D017874:Immediate-Early Proteins / Q000378:metabolism; D007395:Interneurons / Q000737:chemistry / Q000502:physiology; D051379:Mice; D010320:Parvalbumins / Q000032:analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013315:Stress, Psychological / Q000209:etiology*; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D000099184:Serum-Glucocorticoid Regulated Kinases
D017874:Immediate-Early Proteins; D010320:Parvalbumins; D017346:Protein Serine-Threonine Kinases; D011965:Receptors, Glucocorticoid; D044767:Ubiquitin-Protein Ligases; D000099184:Serum-Glucocorticoid Regulated Kinases; C502429:Ube3a protein, mouse