Rett syndrome disrupts brain development in specific areas: Study
Immature nerve cells found to increase in region linked to epilepsy
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In Rett syndrome, certain brain cells that form before birth and mature slowly remain immature and do not develop normally, suggesting that the condition disrupts brain development in specific areas rather than the entire brain, according to a mouse study.
By studying female Rett mice after symptoms appeared, researchers found that immature nerve cells increased specifically in a region of the brain called the piriform cortex, which is linked to epilepsy. These cells were smaller and less complex, while other brain regions involved in generating new nerve cells remained unaffected.
“Our findings support the notion that the protracted maturation process of immature populations of embryonic origin is especially vulnerable [in Rett],” the researchers wrote.
The study, “Doublecortin-expressing cells are selectively altered in the piriform cortex but not in neurogenic areas of symptomatic Mecp2-heterozygous mice,” was published in the journal Neuroscience.
Rett caused by mutation in key gene
The most common cause of Rett syndrome is mutations in the MECP2 gene, which normally helps to control when other genes are turned on or off. This control is essential for healthy brain function.
Rett syndrome mainly affects girls and usually appears after a period of normal early development. Between about 6 months and 18 months of age, Rett children begin to lose skills they had already gained, such as speech and hand use. Other common disease features include learning difficulties, repeated hand movements, impaired breathing, and problems with movement and coordination.
Because symptoms start later, it’s thought that Rett is not caused by a failure to form brain cells, but rather by problems maintaining mature brain cells.
In previous work, researchers in Spain found that mice lacking MeCP2 had more immature neurons (nerve cells) than normal in certain brain areas. These immature nerve cells were identified using a biomarker called doublecortin (DCX).
In healthy mouse brains, DCX-positive cells are usually found in areas where new neurons are made. There is also a distinct group of DCX-positive cells in the piriform cortex, a region of the brain involved in the processing of smell and memory, as well as in certain types of epilepsy. Unlike new neurons, these cells are created before birth and mature very slowly, continuing to develop well into adulthood.
Research suggests that this slow-maturing group of neurons is especially important because similar cells may exist in the human brain. As such, studying them can help scientists understand brain disorders that affect neuronal development, including Rett syndrome.
Increase in type of immature neuron found in specific brain area
The team has now investigated older Rett female mice with symptoms to see whether these immature neurons appear later, helping to clarify how MeCP2 affects brain cell maturation over time.
According to the analysis, DCX-positive immature neurons were present in the same brain areas in both Rett mice and healthy mice, and the total number of these immature cells was similar. Even so, in the piriform cortex of Rett mice, there was an increase in a more developed, complex type of immature neuron.
This change was not observed in brain regions where new neurons are normally generated, such as the dentate gyrus of the hippocampus, which is vital for learning and memory, and the ventricular-subventricular zone, which contains precursor cells that divide into neurons.
Even though more of these developing cells were forming, they didn’t grow normally. They had smaller, simpler shapes with fewer branches (dendrites) that help them connect with other brain cells. In other words, the cells are being made, but they’re not maturing properly.
These structural changes in neurons were not observed throughout the brain. In the dentate gyrus, the number and appearance of DCX-positive cells stayed normal even when MECP2 was missing.
Overall, these findings support the idea that MECP2 plays an essential role in the slow, long-term development of brain cells. Instead of helping new cells form, MECP2 helps brain cells finish maturing over time.
“Future studies are needed to clarify the molecular causes of these local impairments and the potential consequences of these deficits in the neural networks,” the researchers concluded. “This way, we may contribute to [identifying] new therapeutic targets aimed at promoting neuronal maturation in Rett syndrome.”
