No Differences Among Sexes Found in Memory Tests Given Mouse Model

Angelman syndrome research into how disease manifests among males, females

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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An illustration shows a mouse in a person's hand near test tubes.

In a mouse model of Angelman syndrome, male and female mice show similar responses in tests of memory and fear, a study found.

“Our results support the general conclusion previously reported in the field that there is no clear sex difference in fear-conditioning learning in [Angelman] mice,” the researchers wrote.

Findings indicate that a protein called SK2 is involved in abnormal brain activity and memory impairment in these mice across sexes.

The study, “Lack of UBE3A-Mediated Regulation of Synaptic SK2 Channels Contributes to Learning and Memory Impairment in the Female Mouse Model of Angelman Syndrome,” was published in Neural Plasticity.

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Males and females show similar ‘fear-conditioned learning’ responses

The frequency of Angelman syndrome does not vary according to sex, but some emerging research in people with the condition and in animal models suggests there may be differences in how Angelman manifests between males and females.

A team of researchers at Western University of Health Sciences, in California, had previously shown that the SK2 protein is dysregulated in male mice harboring Angelman-causing mutations in the UBE3A gene, and that SK2 abnormalities contributed to problems with memory in these mice.

Here, the scientists conducted a series of studies to assess whether this same phenomenon also occurred in a female mouse model.

The SK2 protein is normally located at synapses, the points where individual nerve cells come into contact and release chemical messengers to communicate with each other. Results showed that female Angelman mice had increased levels of SK2, similar to what was seen in male mice.

Analyses of neurons (nerve cells) in the hippocampus — a brain region that plays a central role in memory — indicated that female mice with Angelman had significantly reduced long-term potentiation (LTP), but significantly increased long-term depression (LTD).

LTP is a phenomenon where the signaling power at a synapse becomes stronger as more signals are sent, which is thought to be critical in the formation of memory. LTD is a related process where signals at a synapse cause a subsequent decrease in synapse activity.

Treating the cells with a molecule that inhibits SK2, called apamin, led to a normalization of neuronal activity (that is, more LTP and less LTD) in the female Angelman mice.

In a test of memory where mice were trained to have a fear response (freezing) in response to a sound, the female mice with Angelman showed marked deficits compared to healthy (wild-type) mice. When the mice were treated with apamin, their performance on these tests improved significantly.

The findings here in female mice were largely consistent with prior results in male mice, although “subtle differences” were evident between the sexes, the scientists said. For example, they noted that the reduction in LTP was generally less severe in females compared to males, which the scientists speculated could be due to variances in levels of the hormone estrogen, which has been shown to affect LTP.

Despite these small differences in neurological activity, “the general conclusion seems to be that there is no sex difference in fear-conditioning learning and that both male and female [Angelman] mice are equally impaired,” the researchers wrote.

A study limitation is that results in female mice were compared with previous data from males, rather than comparing the two sexes in simultaneous tests, the scientists noted. They also noted that female mice were not analyzed based on hormone cycles, but since results showed little difference between sexes with very different hormone levels, the researchers didn’t think this likely to have influenced the results.