By Emily Leclerc | Waisman Science Writer
Science is often the art of understanding how much we do not know. The cause of Down syndrome (DS) – an extra copy of the 21st chromosome – was discovered in 1959 and yet, 66 years later, the condition’s impact on brain development is relatively unknown. Decades of research is still not enough to unravel the complexities of DS’s influences on the brain’s journey from infancy to maturity. “There is just not a lot out there right now because the field is still very much in its early years,” says Matthew Russo, PhD, postdoctoral fellow in the lab of Waisman Center investigator Anita Bhattacharyya, PhD.
A new review paper published in Nature Reviews Neuroscience from Bhattacharyya, associate professor of cell and regenerative biology, pulls together what is currently known about DS’s impact on brain development. “This review focuses mostly on research in either post-mortem human brain tissue or in induced pluripotent stem cells (iPSCs),” says Russo, first author on the paper. “We have gotten some insights from mouse models but there are certain caveats with those. Some of the things we thought we knew from mouse models are more nuanced in the human brain or in human cells.” Waisman investigator André Sousa, PhD, assistant professor of neuroscience, collaborated with Bhattacharyya and Russo on the paper.
Even with the limited research available, it is clear that DS’s impact on brain development is complex and system wide. It touches every part of the genome, the cell, and the brain and it will likely take many more years of work to fully disentangle. But we do know a few things.
A difference in numbers
It has been consistently shown that individuals with DS tend to have lower brain volume than typical individuals. This is due to there being fewer cells in the brain of individuals with DS. The best theory at the moment for why this happens is that during prenatal development, the cells that are building the brain experience something called impaired neurogenesis.
Neurogenesis is the process through which neurons develop from progenitor cells. A neural progenitor cell is a stem cell that is destined to become a neuron. During prenatal development, the neural progenitor cells divide rapidly in the brain to create a large pool of cells. Then those progenitor cells begin to differentiate and develop into specific neurons in the brain. “We think that the basis for altered brain size and number of neurons comes down to the earliest steps in building the brain,” Bhattacharyya says. “A smaller pool of neural progenitor cells would lead to fewer neurons. We still need to understand if, when, and how there are fewer progenitors during DS brain development.” Evidence of different options have been found in analysis of post-mortem tissue as well as in models developed from iPSCs. Even so, the results from various studies don’t always agree and there are important limits that can inhibit post-mortem and iPSC analyses.
Researchers also have almost no understanding of the exact biological reason why DS would affect neurogenesis. Deeper analysis of the genetic signals driving progenitor cell differentiation and their cell cycle is needed to begin to unravel that mystery.
Neurons are also not the only type of brain cell shown to be impacted. A large portion of the brain is made up of glial cells – support cells that ensure that the neurons and their connections are structurally sound and operating properly. There are different types of glial cells that perform several different functions such as aiding with neuronal communication, providing nutrients and structural support, defeating pathogens, and producing cerebrospinal fluid.
Evidence from studies on both post-mortem tissue and stem cells suggest that individuals with DS produce more glial cells than typically developing individuals. Several studies of post-mortem tissue have reported these increased numbers of glial cells, but the analysis used has important caveats that have the potential to incorrectly represent the number of cells. Studies using iPSCs have also shown increased glial numbers but are still incapable of revealing why exactly this is occurring. “Having the incorrect balance of the number of glial cells to neurons can dramatically change how the connections between neurons function and so it’s important to establish the facts,” Bhattacharyya says.
A potential theory is that there is something interfering with the switch from neurogenesis to gliogenesis. During that switch, the progenitor cells stop making cells destined to become neurons and instead begin producing cells destined to become glia. There are sparse results insinuating this could be where the problem lies but nothing conclusive has been found yet.
A harder time connecting
Neurons form connections with each other through synapses. Synapses are the connectors, junctions, and interchanges between cells. They are how neurons communicate with one another and create the larger more complex neural pathways throughout the brain.
In individuals with DS, fewer synapses and impaired synaptic function are thought to be key drivers of the intellectual disability in DS. “There is a sort of consensus in the field that says neurons that have Trisomy 21 have fewer synapses,” Russo says. “But we don’t know what things are driving that. We don’t have a mechanism for it yet.” The lower density of synapses and the imbalances that it causes in the different types of neurons is thought to be a crucially important reason as to why there is altered brain function in DS.
There has also been important evidence presented that the synapses in an individual with DS don’t function as well as those in a typical brain. The chemical signals used in synapses have been shown to be disrupted along with the cell’s electrical signaling. This makes it harder for neurons to communicate with each other which leads to wider spread disruptions of brain circuitry. And as Russo said, researchers do not know why this happens yet. One of the current thoughts is that the genome-wide alterations that DS causes have an important impact on synaptic development but no candidate genes or causes have been presented. This emphasizes the need for a better understanding of the broader impacts of DS on the genome as a whole.
“With all of the new molecular biology techniques that are out there now, there is the capability for a lot more research with these more powerful and expansive tools,” Russo says. “We are getting better answers for what is going on in the genome but not a whole lot of it has been published yet.”
Variations in a strict timeline
One of the more general points that the review paper makes is that, due to the genome-wide disruptions caused by DS, some of the timing during brain development may be off. Brain development is a tightly controlled series of complex steps that all have to take place perfectly and at the exact right time for everything to function properly. If anything is off throughout that process it can cause disruptions and abnormalities. The term for that timing is heterochrony.
“The general idea is that when the brain develops, a relatively small number of neural progenitor cells divide, creating more neural progenitor cells, and those eventually become neurons. Heterochrony is a little easier to understand if you think about a single neural progenitor going through this process. It will divide into more neural progenitors, some of which will start turning into neurons and others that will continue to divide to produce more additional progenitors. At a certain point in development, the progenitors will switch over to producing glial cells.” Russo says. “The premise behind heterochrony in DS is that all of that still happens but the switch to turning into neurons and then turning into glial cells happens earlier than it is supposed to.” That difference in developmental timing could be playing a huge part in the differences seen in DS. Several algorithms have been used to investigate this but properly studying development over the needed time frame is tricky. So, there are limited studies and results at this time. Much more work needs to be done to determine if this is truly a phenomenon that is occurring.
Much more to discover
Even as Bhattacharyya and Russo’s review paper lays out what is known, it deeply underscores how much is unknown. Researchers are just beginning to scratch the surface on brain development in DS with so much left to uncover.
“As we were assessing literature for this review, we found that there was actually little data to support the features of DS that the field views as established,” Bhattacharyya says. “We hope that by highlighting this, the field will work to address the unknowns.”