July 16, 2021


by: admin


Tags: Autism, critical, flagged, genes, influence, Spectrum, time, window


Categories: autism

Vital time window flagged for autism gene’s affect | Spectrum

New neighbors: transplanted immature inhibitory cells (red) surround a mature neuron (dark gray); the new cells appear to prevent signal imbalance in mice lacking a copy of the autism-related FOXG1 gene.

Mice lacking a copy of the autism-related gene FOXG1 in the brain have atypical social behavior and an imbalance in excitatory and inhibitory signals, according to a new study. The transplantation of wild-type inhibitory neurons into the animals between their first and second week of life prevents these differences from occurring, as the study also shows.

The results show a critical window of time for FOXG1 during neurodevelopment. Mutations in the gene cause a rare form of autism called FOXG1 syndrome.

The researchers who led the new work hypothesized that the gene leads to characteristics of autism by disrupting the development of circuits containing the inhibitory chemical messenger gamma-aminobutyric acid (GABA). Too few GABA-producing cells could lead to an imbalance between excitatory and inhibitory brain signals, which has been linked to autism.

Impairments in these GABAergic cells, according to previous work on mice, contribute to other conditions associated with autism, including Rett syndrome and Angelman syndrome. And too much FOXG1 appears to cause overgrowth of GABAergic neurons in organoids derived from cells of autistic people with no known mutations associated with autism.

“We already had this GABAerge hypothesis, and we had this FOXG1 gene on top of that, so we wanted to put it together,” says lead researcher Goichi Miyoshi, assistant professor of neurophysiology at Tokyo Women’s Medical University in Japan. “Maybe there is a link.”

Social tests:

To make the connection, Miyoshi’s team created novel mice that were missing a copy of FOXG1 in some or all of their cells. In contrast to controls, mice lacking the gene throughout the body had no preference for interacting with another mouse over an empty cage, a sign of atypical social behavior. They also had fewer GABAergic neurons and smaller brains than the controls.

But mice lacking the gene only in GABAergic cells didn’t show any of the social differences, which was puzzling, says Miyoshi. However, when he and his colleagues removed the gene from both inhibitory and excitatory cells, the social differences returned.

“This is another puzzle,” says Myoshi. “We’re trying to understand why.”

All FOXG1 mice showed signal imbalance only as adolescents, although the behavioral differences occurred in adults. The team found that they could block both signal imbalance and atypical social behavior by transplanting immature GABAergic cells from wild-type mice into the cortex of 1-week-old FOXG1 mice. Transplanting the cells after 3 weeks had no effect.

When the team manipulated wild-type mice to overexpress FOXG1 in both inhibitory and excitatory cells, these mice also showed differences in social behavior – but only when FOXG1 was overexpressed at 1 to 2 weeks of age. Overexpression of the gene in mice older than 2 weeks had no effect.

The results were published in Nature Communications in June.

Possible interventions:

The fact that behavioral differences only occur when the gene is changed in both types of neurons is “fascinating,” says Flora Vaccarino, professor of neuroscience at Yale University and lead researcher on the Organoid study, which is not involved in the new work was.

While some of the effects are subtle and need further study, the study is “the first time we’ve actually had a clue” of how the gene contributes to autism.

Identifying a critical time window for FOXG1’s role in brain development gives hope that interventions could help children with FOXG1 syndrome, says Ilaria Meloni, an adjunct professor of medical genetics at the University of Siena in Italy who was not involved in the study.

Because many features of the syndrome are severe, researchers have asked if postpartum interventions might have any benefit, Meloni says.

“This indicates for the first time that we have a real-time window for intervention,” she says, adding that the new mouse models will be useful for future work.

Miyoshi speculates that FOXG1 is critical to a small subset of both inhibitory and excitatory cells that help build brain circuits early in development. His team is working to identify this subgroup that may have implications for autism beyond FOXG1 syndrome.

Quote this article: https://doi.org/10.53053/BLQG5882


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