Could understanding the ebb and flow of calcium in brain cells provide clues that help researchers develop a treatment for a devastating neurological disease?
Rett syndrome, a rare, non-inherited neurological disorder that mostly affects girls and causes severe deterioration in their ability to speak, eat, move and even breathe easily is caused by variations in the MeCP2 gene.
A recent study, led by researchers at the Waisman Center, is the first to uncover the molecular underpinnings of how variations in MeCP2 can affect calcium dynamics in astrocytes, a specific kind of cell in the brain and spinal cord.
“This study highlights a potential link between defects within astrocytes that have variations in MeCP2 and more widespread problems in the brains of individuals with Rett syndrome,” says Qiang Chang, senior author of the new study, a Waisman Center investigator and the new director (as of July 1, 2018) of the center.
Better understanding how Rett syndrome affects different cells within the brain can yield valuable insight and aid efforts to design new and more effective therapies.
But researchers have had a difficult time completing the puzzle of how variations in MeCP2 lead to Rett syndrome because the MeCP2 gene is active in all types of cells in the brain.
“Initially Rett syndrome research focused on what was happening in neurons,” says Chang, an associate professor of medical genetics and neuroscience. “It’s only recently that we and others have started exploring what happens in astrocytes as well.”
Astrocytes are star-shaped cells that reside throughout the brain and spinal cord. They were previously thought to be mere “gap-fillers” but researchers now think they have a wide array of important functions.
The new study showed that loss of MeCP2 in astrocytes changes the calcium dynamics within these cells. Calcium signaling is an important way for different kinds of cells in the brain and nervous system to communicate with each other.
Based on their findings, Chang and his colleagues think that in indivuduals with Rett syndrome, astrocytes make more of a protein called TRCP4. This protein is part of structures that regulate the flow of calcium into major storage compartments within cells.
The presence of more TRCP4 increases the amount of calcium within astrocytes, leading to more calcium fluctuation in the cells. The resulting aberrant calcium signaling hyper-activates specific molecules called NMDARs on neighboring neurons.
In addition to hyperactivating NMDARs, the abnormal calcium dynamics in astrocytes makes the neuronal network more excitable.
“Increased neuronal network excitability maybe related to seizures, which affect many individuals with Rett syndrome,” says Chang.
His lab is now testing several small molecules to see if any of them can rectify the aberrant calcium dynamics observed in astrocytes and ultimately help individuals with Rett syndrome with seizures and other the medical challenges.
“To effectively treat Rett syndrome, I think we will have to address the deficits in all the different types of cells that are affected,” says Chang. “If we only address issues in neurons, that’s not going to work, because there will still be problems with the astrocytes. So it’s critical that we understand the astrocyte side of the story as well.”
To observe how lack of MeCP2 affects astrocytes, researchers used induced pluripotent stem cells. These stem cells were derived from skin cells donated to the Chang lab by individuals with Rett syndrome.
Using astrocytes derived from stem cells allowed Chang and his colleagues to be among the first to observe how variations in MeCP2 affect astrocytes specifically without influence from nearby neurons.
“During typical development, neurons develop first followed by astrocytes,” says Chang. “So in patients or in animal models, by the time astrocytes develop, these cells have already been exposed to neurons.”
If these neurons had variations in MeCP2, it would be difficult to parse out which aspects of astrocyte biology were specific to the cells as opposed to being indirectly affected by the surrounding defective neurons. Using stem cells, Chang’s group could observe astrocytes without any potential influences from nearby neurons.
The researchers confirmed their findings in human stem cell-derived astrocytes with animal models as well. “We observed the same [calcium dynamics] from human cells to mouse cells and in the mouse brain and even in live mice,” says Chang. “This consistency makes us believe that we have novel findings with important implications for Rett syndrome.”