Now scientists have found a way to give mice ASD, and the mice are teaching us something about brain development and the autism spectrum. According to a new study published in Nature Communications back in June, mice missing a copy of the autism-linked gene FOXG1 in the brain have atypical social behavior and an imbalance in signals which affect interest and inhibitions. The study also found transplanting “wildtype inhibitory neurons” into the animals between their first and second weeks of life prevents these differences from occurring. These results pinpoint a critical time window for FOXG1 during neurodevelopment. Mutations in that gene cause a rare form of autism known as FOXG1 syndrome.
The researchers who led this study suspected the gene leads to traits of autism by disrupting the development of circuits involving the inhibitory chemical messenger gamma-aminobutyric acid (GABA). Having too few GABA-producing cells could result in an imbalance between excitatory and inhibitory brain signals, which is linked to autism. Impairments in these cells contribute to other conditions linked to autism according to previous work in mice, including Rett and Angelman syndromes. Too much FOXG1 appears to cause an overgrowth of GABAergic neurons in organoids derived from cells of people with autism with no known autism-linked mutations. This means scientists have found a way to create autism, and this can be a step in developing early interventions.
To get the connection, the team created “novel mice” – missing a copy of FOXG1from some or all of their cells. Mice missing the gene throughout their bodies preferred not to interact with another mouse, choosing instead an empty cage, which is a sign of atypical social behavior, and also had fewer GABAergic neurons and smaller brains. Lead researcher Goichi Miyoshi, an assistant professor of neurophysiology at Tokyo Women’s Medical University in Japan, says the mice missing the gene only in GABAergic cells didn’t show any social differences but they returned when they removed the gene from both inhibitory and excitatory cells; like many aspects of ASD the reasons are not yet clear.
Timing played a crucial role in the study: the FOXG1 mice showed a signaling imbalance only as juveniles, even though the differences in behavior appeared in the adult mice. The research team found out they could block both traits by transplanting immature GABAergic cells from wildtype mice into the cortex of FOXG1 mice when they were one week old. Transplanting the cells at 3 weeks of age had no effect. When the team manipulated the wildtype mice to overexpress FOXG1 in both inhibitory and excitatory cells, they also showed differences in social-behavior, but only when the gene was overexpressed between 1 to 2 weeks of age. Overexpressing the gene when they were older had no effect.
Flora Vaccarino, a professor of neuroscience at Yale University and lead investigator on a prior organoid study, says the fact that these behavior differences occur only when the gene is altered in both types of neurons is intriguing. Although some of the effects are subtle and should be investigated further, this particular study is the first time we have an inkling of precisely how this gene is contributing to autism. Ilaria Meloni, an associate professor of medical genetics at the University of Siena in Italy who has conducted other research, says identifying a critical time window for FOXG1’s role in brain development offers hope that interventions could help children with FOXG1 syndrome. She also says that because many traits of FOXG1 syndrome are severe, researchers have questioned if intervening after birth is beneficial at all, but that the work suggests a real window for intervention for the first time ever and the new mouse models will be useful for future work.
Miyoshi suspects FOXG1 is crucial for a small subset of inhibitory and excitatory cells that help build brain circuits early in development and his team is working on identifying the subset, which in turn could have implications for autism beyond FOXG1 syndrome. So, don’t be afraid of mice: they are helping in the fight to manage autism.
Recent Comments