Why would a successful college student abruptly stop attending class, ignore his roommates, and begin hallucinating? How does an elderly woman suddenly forget how to navigate a route she has routinely driven for years?
These two hypothetical scenarios seem unrelated. The student’s behavior suggests schizophrenia, typically diagnosed in people in their twenties and thirties, while the woman exhibits a classic symptom of dementia, which is more common in the elderly. But researchers from the Broad Institute and Harvard Medical School have uncovered a link between the two conditions. Although the initial focus of the study was on the roots of schizophrenia, the group found some surprising similarities between the brains of patients with schizophrenia and those of healthy older adults.
Flier professor of biomedical science and genetics Steve McCarroll, who previously published groundbreaking work on the genetic roots of schizophrenia, aimed to characterize the biological changes associated with schizophrenia at the level of individual cells. “Knowing the genes is just the first step,” he said.
The next step is to learn which genes get turned on in cells, a process termed gene expression. Emi Ling, a postdoctoral fellow who worked closely with McCarroll and associate professor of psychiatry Sabina Berretta on the project, used single nucleus RNA sequencing to measure and track gene expression in the nucleus of every cell in a tissue sample. (The tool, called Drop-seq, was invented at Harvard Medical School during a collaboration between McCarroll’s lab and that of Mallinckrodt professor of physics and applied physics David Weitz.) Because RNA is the intermediary between the blueprint contained in the cell’s DNA and the final protein products made in each cell, sequencing the RNA reveals which genes are active. RNA levels can thus be used to detect patterns in gene expression.
Ling examined postmortem brain tissue from 94 individuals with schizophrenia and 97 people without any psychiatric diagnoses, ranging in age from 22 to 97 years. The team focused only on tissue from the dorsolateral prefrontal cortex, which is known to be responsible for memory, attention, and executive functions—skills that decline in patients with schizophrenia.
Such analysis generates massive quantities of data: the scientists sequenced RNA from more than a million brain cells, and each cell synthesizes hundreds of RNA messages encoding different proteins. The researchers carefully tracked which of the cells came from schizophrenic patients or from healthy controls.
To analyze their data, Ling and her colleagues employed a technique called “latent factor analysis,” which helps identify common patterns. Since different genes often work together in biological pathways, and different cell types often collaborate to perform essential functions in the body, the team was very interested in any signs that genes related to schizophrenia—a notoriously complex disease—might work in concert across different cell types.
What they discovered was a remarkable synchronization in gene expression between neurons and astrocytes. Neurons are the primary functional units of the nervous system, while astrocytes are necessary for the formation and function of synapses, junctions where signals are transmitted between nerve cells or from nerve cells to target cells, such as muscle cells.
When neurons turned on a distinct set of genes encoding proteins used as building blocks in these synapses, astrocytes also revved up a different set of genes critical to synaptic function. For example, neurons expressed genes resulting in proteins needed by the presynaptic vesicle for uptake, storage, and release of neurotransmitters. At the same time, astrocytes provided most of the fatty acids and cholesterol needed to form these junctions. “This was a really interesting finding,” said Berretta, “because typically we have focused research on neurons. But the field has recently evolved to think about the importance of glial cells”—supporting cells of the nervous system that don’t produce electrical impulses, among them, astrocytes. The scientists named the phenomenon they’d observed the synaptic neuron and astrocyte program (SNAP).
What does SNAP have to do with schizophrenia? Several of the SNAP genes expressed by neurons and astrocytes have been previously linked to the disease. But an additional finding suggests potential new avenues for treatment. Patients with schizophrenia had less SNAP: lower levels of expression of these genes in both neurons and astrocytes.
“I think it is interesting to think about the possibility of SNAP-promoting therapies—to try to develop medications that would promote SNAP,” McCarroll said. He added that SNAP may explain why some behavioral factors are broadly protective against mental illness. “Sleep is protective, but we don’t know why,” he pointed out. “SNAP is potentially a mechanism for some of these mental-health-promoting behaviors.”
And then there was the final discovery. Patients with schizophrenia weren’t the only ones with low levels of SNAP. Many, but not all, of the elderly patients from the control group showed similar declines in SNAP expression. “We were not expecting it, but it makes sense,” said Berretta, since patients with schizophrenia have a high risk for developing dementia. McCarroll also pointed out that similar findings (such as cortical thinning and loss of dendritic spines of neurons) from MRI and other types of brain scans have been observed in patients with both Alzheimer’s disease and schizophrenia.
Berretta said the similarity in SNAP expression between schizophrenia and aging raises intriguing avenues of exploration into the causes and treatment of additional psychiatric disorders. “We’re not necessarily saying these changes are unique to schizophrenia,” she explained. Might patients suffering from age-related dementia also benefit from SNAP-promoting therapy? There could be “a point of convergence, perhaps in different types of brain pathology,” and even in other regions of the brain beyond the one they studied. The intriguing possibility is that a better understanding of SNAP deficiency might help unravel other puzzling diseases of the brain—and lead to treatments that could prove broadly protective against mental illness.
