Response to acute stress may be altered in AS, mouse study says

Findings suggest treatment approach of targeting glucocorticoid receptors

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The response to acute stress may be altered in Angelman syndrome (AS), a preclinical study suggests.

In a mouse model of the disorder, researchers found that the brain’s response to acute stress hormones (glucocorticoids) was enhanced. This was reflected by a more pronounced pattern of gene activity in response to the hormones among AS mice relative to healthy mice, but such differences weren’t observed after chronic exposure.

The findings suggest that in the brain, a role for ubiquitin protein ligase E3A (UBE3A) — the loss of which is a hallmark of AS — is to regulate signaling at the receptors that mediate stress responses.

“We believe that our findings contribute to a better understanding of the molecular mechanisms of altered glucocorticoid responsiveness in AS,” researchers wrote, noting that approaches to dampen this response could help ease anxiety and stress in patients living with the disorder.

The study, “The Hippocampal Response to Acute Corticosterone Elevation Is Altered in a Mouse Model for Angelman Syndrome,” was published in the International Journal of Molecular Sciences.

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UBE3A may help regulate receptors that mediate effects of stress hormones

AS is caused by genetic defects that lead to a missing or malfunctioning UBE3A in mature nerve cells of the brain. UBE3 is an enzyme that plays an important role in targeting damaged or unneeded proteins for degradation. Evidence suggests that UBE3A may also work as a transcriptional co-regulator, meaning it works collaboratively with proteins called transcription factors to influence gene activity.

It’s been proposed that UBE3A may regulate activity at glucocorticoid receptors (GRs), which are transcription factors that mediate the effects of glucocorticoid hormones like cortisol, the body’s main stress hormone.

In line with that hypothesis, UBE3A deficiency in AS mouse models has been linked to disrupted GR signaling in a brain region called the hippocampus, as well as alterations to GR-associated functions including anxiety, memory, sleep-wake rhythms, and metabolic processes in the liver.

However, the molecular mechanisms that might underlie UBE3A modulation of GR signaling in AS aren’t fully understood, which the researchers aimed to better understand in the study.

In cell culture experiments, the scientists found that UBE3A interacts with GRs and influences their response to cortisol, altogether supporting a role for the enzyme as a regulator of GR activity.

In a mouse model of AS, the levels of corticosterone (CORT; the mouse version of cortisol) were significantly reduced in the mornings compared with healthy, or wild-type, mice but were similar in the evenings, when CORT levels are typically higher. That finding reflects an overall disruption of normal CORT dynamics in AS, the researchers noted.

Next, the researchers examined whether the response to CORT exposure in the hippocampus would be different between AS and wild-type mice. They looked at the expression, or activity, of genes in that brain region after mice were injected with a single, acute dose of the hormone.

Results showed a significant difference in gene activity patterns in AS compared with wild-type mice after the exposure. In particular, while expression of 283 genes changed in wild-type mice after being exposed to CORT, 2,910 genes showed altered activity in the AS mice.

Ultimately, the researchers identified 1,208 genes which were thought to contribute statistically to the different response to CORT observed between healthy and AS mice.

“This treatment affected 10 times as many genes in the AS hippocampus as in [wild-type], which suggests that under normal circumstances UBE3A limits GR signaling in the mouse hippocampus,” the researchers wrote, adding “AS mice are more sensitive to acute glucocorticoid exposure.”

Affected genes were largely involved in transcriptional regulation — the regulation of gene activity — and synaptic transmission, the process by which nerve cells chemically communicate with each other. A deeper analysis revealed that altered genes were expressed in a range of different cell types in the hippocampus, including non-neuronal cells.

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Findings could lead to treatment strategies that alleviate stress and anxiety

In contrast to the acute exposure, chronic CORT, administered continuously for five days, did not elicit the same differences between AS and wild-type mice.

Chronic CORT exposure did lead to some divergence in gene activity within the livers of AS mice compared with wild-type mice, which is consistent with the susceptibility for liver dysfunction in AS, the researchers noted.

Overall, “our current study provides novel insight into the molecular interaction between the UBE3A and GR,” the researchers wrote.

Given the “altered glucocorticoid sensitivity in AS mice,” a treatment that blocks GR signaling should be investigated in the mouse model, the team added.

Since GR plays an important role in the body’s stress responses, “such treatment strategies could potentially benefit AS patients that suffer from stress and anxiety symptoms,” the team concluded.