Scientists Discover a Neuron That May Play a Role in Schizophrenia
A new 3D map of the brain's movement center is already generating discoveries.
A variety of psychiatric diseases—schizophrenia, depression, and addiction—have roots in part of the brain typically associated with movement known as the basal ganglia. Neuroscientists aren’t sure exactly how dysfunctions become disease or which specific nerve cells are involved, but a new map of the region’s cells and their genes could help solve those mysteries. Among those cells is a newly identified rare subtype of neuron potentially associated with the genetic risk of developing schizophrenia.
The new map, which took 10 years to create, is part of an effort by hundreds of scientists around the world who are trying to create a detailed 3D genetic map of the brain. The effort, known as the BRAIN Initiative Cell Atlas Network, has been likened to the Human Genome Project, and the basal ganglia was their first step. The results were published November 12 in a collection of nearly 30studies in the journal Cell.
The special neuron potentially connected to schizophrenia is “a great example of the types of observations that can be mined from this incredibly rich dataset,” says neuroscientist Talia Lerner at Northwestern University who was not involved in the work. But at the same time, she says, “follow-up studies would be needed to better understand the link to disease.”
(Schizophrenia in women is widely misunderstood—and misdiagnosed.)
Scientists focused on the basal ganglia because they wanted to better understand what types of cells make up its structures, how similar they are between humans and other primate species, and whether identifying their characteristics could help researchers better understand psychiatric disorders.
“The biggest gap in the community is the lack of a common understanding of how many cell types are in the human brain and whether we ever have gained a comprehensive understanding or not,” says Hongkui Zeng, a molecular and cell biologist who is the executive vice president of the Allen Institute. The ultimate goal of creating this “cell-type atlas,” she says, is for the entire research community to use it to guide their own work from now on.
To make the map, the researchers studied 25.5 million individual cells obtained from brain tissue, including 21.0 million cells from humans, 3.0 million from rhesus and cynomolgus macaques, and 1.5 million from common marmosets. With this information, scientists mapped different cells’ location and identified which genes within them were active—which serve as a reference for studying the brain andwhat makes human brains unique.
Studying how human brain cells function is extremely complicated, mainly because some experiments that could show the cell’s functioning cannot be performed on living human brains. At the same time, studies of postmortem brain tissue cannot provide a complete picture of how cells actually function. “The ability to study the human brain itself is very very limited,” Zeng says. That is why studies using animal models from different species are the best way to understand the different regions of the brain and their cells, how they interact with each other, how they generate all kinds of behavior and cognition, and how those functions change under disease conditions, she says.
A full picture of the cells that populate different parts of the brain is key to those studies, as well. Labs used the atlas to examine various disease connections, including genes linked to autism, an updated gene therapy for Parkinson’s, and a better understanding of aging in the brain.
One of the groups, led by neuroscientist Nelson Johansen of the Allen Institute, sequenced genetic material from a fraction of cells in the new atlas across humans, macaques, and marmosets. Their analysis revealed which neurons remained unchanged through primate evolution and which ones had new and different characteristics—pointing to the biological mechanisms behind psychiatric disorders in people.
In their analysis, they found a rare type of neuron called STR D2 SMYD2-HTR7 that’s located in the striatum, one of the points where information enters the basal ganglia. The nerve cell carried a combination of genes that caught the scientists’ attention. These genes encode receptors that pick up signals from two neurotrasmitters, dopamine and serotonin, both of which are linked in some way to schizophrenia.
Antipsychotic medications mainly target the D2 dopamine receptors. By reducing their activity, these drugs help control hallucinations and delusions. The serotonin receptor HTR7, on the other hand, has attracted neuroscientists’ attention because it helps regulate mood and cognition, and blocking it with medication helps treating mood, anxiety and other cognitive symptoms.
Johansen and his team compared the cellular data fromthe striatum with large genetic studies of psychiatric disorders and found that genetic risk for schizophrenia was significantly enriched in thisgroup of nerve cells. Although this doesn’t mean that the neurons are directly involved in the disease, Johansen says, future studies should focus on understanding how they interact with other brain cells, whether their activity differs in people with schizophrenia, and whether manipulating them influences disease processes.
Similar methods have previously helped identify other cells potentially associated with schizophrenia. That means “there's a very good chance that the findings are true,” says psychiatrist Laramie Duncan at Stanford University who was not affiliated with the atlas work. “These are cell types that probably truly are important for psychiatric disease.”
Although this is only a first step toward developing treatments in the future, the creation of the new atlas “is a big deal,” Duncan says. Many cell populations are involved simultaneously in the development of psychiatric conditions, and trying to target just one to understand them is almost impossible. The new atlas provides labels that scientists can use to identify those cell types and could eventually help them develop experimental tools that would allow them to manipulate specific targeted cell populations, she says.
For Lerner, an interesting possibility is that scientists could now target specific types of nerve cells through combinations of drugs, brain stimulation, and behavioral interventions. By designing therapies that combine these approaches, scientists could achieve much greater specificity targeting neurons, and the information from an atlas like this one will be one piece of the larger picture of how to treat psychiatric disorders comprehensively, she says. “The more we know about which factors disease-relevant neurons may be responsive to, the more we can fit them into a circuit and think about how to target them for treatment.”
