For People with This Genetic Defect, Overly Chatty Neurons May Underlie Schizophrenia RiskNews
The Context: 1 in 3,000 people has a genetic defect called 22q11.2 deletion syndrome, or 22q11DS, putting them at a greater risk for developing schizophrenia. However, the exact biological mechanisms that underlie this association are not well understood.
The Study: A study in Nature Medicine led by NYSCF – Robertson Stem Cell Investigator Sergiu Pasca, MD, of Stanford University creates brain organoids (3D clusters of brain cells made from stem cells) to study how cells interact in the brains of 22q11DS patients, finding that disruption of a certain gene leads to increased neuron firing – a hallmark of schizophrenia. Treating the cells with antipsychotic medications reversed the dysfunction.
The Importance: This study finds a link between 22q11DS and schizophrenia pathology that could underlie behavioral symptoms, giving scientists a more comprehensive understanding of the biological characteristics that underlie a schizophrenia-affected brain.
People with 22q11DS are 30x more likely to develop schizophrenia – a magnitude that far exceeds that of any other known genetic or environmental factors. What is it about this genetic syndrome that makes schizophrenia so much more common? Dr. Pasca’s study suggests the answer could lie in dysfunction of a single gene that leads to overactive neurons.
Studying Disease with Both Biology and Behavior
Dr. Pasca studies the molecular basis of psychiatric disorders, hoping to better define them by their biological basis rather than their behavioral symptoms.
“Oncologists can learn a lot about the underlying drivers of a patient’s cancer by studying a tumor biopsy,” Dr. Pasca, an Associate Professor of Psychiatry and Behavioral Sciences at Stanford, said in a press release. “But probing the underlying biological mechanisms driving psychiatric disorders is hard, because we don’t ordinarily have access to functional brain tissue from living patients.”
With a stem cell model called organoids, however, scientists can now take a peek inside a patient’s brain without an invasive biopsy.
“We’ve been working from behavior down,” he remarked. “Here, we’re working from molecules up.”
Spheroids, Schizophrenia, and Overactive Neurons
Dr. Pasca’s team made their discovery using cortical organoids, clusters of brain cells made from stem cells that recapitulate the environment of the cerebral cortex, the region most associated with schizophrenia.
The scientists generated organoids from 15 22q11DS patients and 15 healthy controls. Not all of the 22q11DS patients reported showing schizophrenia symptoms, but since all carry the genetic defect, those who were asymptomatic may still develop the disease later on in life.
Upon examining the behavior of cells in the organoids, the researchers noticed that neurons in spheroids made from the 22q11DS patients were four times more likely to fire spontaneously than those in the healthy organoids. Overactive neuronal firing hampers communication in the brain, a bit like a heckler at a show: it makes it harder for the brain to get its message across.
The team suspected this was due to disruptions observed in membrane potential and calcium signaling – factors influence whether or not a neuron fires. When treated with antipsychotics, the cells showed normal membrane potential, calcium signaling, and firing rate.
Finally, the team turned their attention to a gene called DGCR8 that is often deleted in people with 22q11DS.
“DGCR8 is probably the main player in the cellular defects we observed,” said Dr. Pasca.
Just decreasing this gene’s activity in otherwise healthy organoids was sufficient to disrupt membrane potential and caused neurons to increase their firing, suggesting that DGCR8 could be at the root of the dysfunction.
Why it Matters
“We can’t test hallucinations in a dish,” noted Dr. Pasca. “But the fact that the cellular malfunctions we identified in a dish were reversed by drugs that relieve symptoms in people with schizophrenia suggests that these cellular malfunctions could be related to the disorder’s behavioral manifestations.”
The results could also have implications for schizophrenia not caused by 22q11DS.
“Clinically, 22q11DS-related schizophrenia isn’t very different from other forms of schizophrenia,” Dr. Pasca explained. “Some of the mechanisms we’ve identified here may turn out to apply to those more genetically or environmentally complex types of schizophrenia.”
Neuronal defects in a human cellular model of 22q11.2 deletion syndrome
Themasap A. Khan, Omer Revah, Aaron Gordon, Se-Jin Yoon, Anna K. Krawisz, Carleton Goold, Yishan Sun, Chul Hoon Kim, Yuan Tian, Min-Yin Li, Julia M. Schaepe, Kazuya Ikeda, Neal D. Amin, Noriaki Sakai, Masayuki Yazawa, Leila Kushan, Seiji Nishino, Matthew H. Porteus, Judith L. Rapoport, Jonathan A. Bernstein, Ruth O’Hara, Carrie E. Bearden, Joachim F. Hallmayer, John R. Huguenard, Daniel H. Geschwind, Ricardo E. Dolmetsch & Sergiu P. Paşca. Nature Medicine. 2020. DOI: https://doi.org/10.1038/s41591-020-1043-9
Cover photo: A brain organoid. Credit: Pasca Lab, Stanford University.