MECP2 Gene Mutations Alter Nerve Cells and Impair Learning, Mouse Study Finds

Mutations in the MECP2 gene — the most common cause of Rett syndrome — impair the activity of nerve cells in the brain that are important for learning, a study in mice reports.

The findings also suggest a critical time window for treatments to be successful in people with this disorder.

Titled “Maternal Experience-Dependent Cortical Plasticity in Mice is Circuit- and Stimulus-Specific and Requires MECP2,” the study was published in the Journal of Neuroscience.

The MECP2 gene, which produces the MeCP2 protein, is believed to control the activity of many other genes, turning them on or off as required, and to regulate nerve cell function and communication.

Previous research in mice indicated that a normal MECP2 gene is essential for neural plasticity or the ability of nerve cells to adapt in response to the environment — in other words, for learning.

In the new study, a team at Cold Spring Harbor Laboratory found that MECP2 mutations in female mice were linked to their unresponsive to the distress of young pups. To demonstrate this, virgin female mice were placed in the same cage with a mother and her newborn pups. Using their sense of smell and high pitch sounds coming from the pups, these virgin mice (known as surrogate mothers) learned to retrieve the pups and return them to the nest, just like the biological mother would.

Specifically, their new maternal behavior was driven by nerve cells in the brain’s auditory cortex — the part of the brain that processes sound. Such neurons, which contain the protein parvalbumin (PV), suppress the activity of other nerve cells and play a critical role in learning throughout development.

Learning something new happens in a time window of heightened ability to respond in the brain and involves complex brain circuitry changes, the scientists said. They also found that MECP2 mutations led to impaired voice perception through changes involving PV neurons.

The team discovered that when MeCP2 is unchanged in surrogate mothers, inhibitory signaling from PV nerve cells decreases after an encounter with the pups, enabling other neurons to become more responsive.

“The inhibitory networks sort of back off and allow the excitatory activity to be stronger,” Stephen Shea, PhD, the study’s senior author, said in a news story.

In contrast, MECP2 mutations impaired the role of PV nerve cells, leading to early termination of a key time window for learning.

“Our data are consistent with a growing body of evidence that cortical networks are particularly vulnerable to mutations of MeCP2 in PV neurons,” they wrote.

Notably, no differences were seen in brain cells with or without normal MeCP2 prior to pup exposure. According to the team, this draws attention to key periods during development where people with Rett may be more responsive to treatments.

“That suggests that MeCP2 is specifically important during windows of heightened learning. That principle might guide treatments that are focused in time, at certain developmental milestones,” Shea said.