Stanford scientists solve secret of nerve cells marking a form of schizophrenia

When nerve cells aren’t busy exchanging information, they’re supposed to keep quiet. If they’re just popping off at random, like in a noisy classroom, it obscures the signals they’re supposed to be transmitting.

But in the most common genetic cause of schizophrenia, it seems that nerve cells won’t shut up, Stanford University School of Medicine investigators have found. And they think they know why.

One in every 3,000 people carries the genetic defect called 22q11.2 deletion syndrome, or 22q11DS. It’s one of the most widespread chromosomal deletions known to occur in humans. People carrying 22q11DS are at an astonishing 30-fold risk for schizophrenia compared with the general population, dwarfing the magnitude of all other known genetic or environmental risk factors. Plus, some 30%-40% of individuals with this deletion receive a diagnosis of autism spectrum disorder early in their lives.

Until now, nobody understood why this deletion so profoundly elevates the risk for these conditions.

But experiments performed in a study to be published Sept. 28 in Nature Medicine have pinpointed a change in an electrical property of cortical neurons among carriers of the deletion that may explain how they develop schizophrenia, which is characterized by hallucinations, delusions and cognitive decline.

The scientists identified a single gene that appears to be largely responsible for the electrical abnormality.

Instead of describing psychiatric disorders as collections of behavioral symptoms, Sergiu Pasca, MD, associate professor of psychiatry and behavioral sciences, envisions defining these psychiatric diseases in terms of their molecular underpinnings — what he calls molecular psychiatry.

“Oncologists can learn a lot about the underlying drivers of a patient’s cancer by studying a tumor biopsy,” Pasca said. “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.” But a new technology circumvents that difficulty.

“We’ve been working from behavior down,” he said. “Here, we’re working from molecules up.”

Experimenting on balls of brain cells

The Stanford scientists, collaborating with researchers from other institutions, uncovered the electrical defect in nerve cells, or neurons, by generating and manipulating tiny spherical clusters of brain cells in a dish. Each cluster contained hundreds of thousands of cells. These so-called cortical spheroids, composed of neurons and other important brain cells, were first developed by Pasca several years ago. Derived from skin cells and suspended in laboratory glassware, the spheroids self-organize to recapitulate some of the architecture of the human cerebral cortex, a brain region often associated with schizophrenia symptoms. The spheroids continue to develop for months and even years in a dish.

In the study, Pasca and his colleagues generated cortical spheroids from skin cells taken from 15 different 22q11DS carriers and 15 healthy control subjects. Pasca, the Bonnie Uytengsu and Family Director of the Stanford Brain Organogenesis Program, is the study’s senior author. Lead authorship is shared by Stanford graduate student Themasap Khan; Stanford postdoctoral scholar Omer Revah, DMV, PhD; and Aaron Gordon, PhD, a postdoctoral scholar at UCLA.

Not all the 22q11DS donors had manifested schizophrenia’s hallmark symptoms. Whereas schizophrenia usually reveals itself in late adolescence or early adulthood, even asymptomatic 22q11DS carriers remain at elevated risk of developing schizophrenia throughout their lifetimes.

The neurons generated from every 22q11DS carrier in the study demonstrated a consistently less-than-normal voltage difference between the inner-facing and outer-facing sides of the cell membranes when the cells weren’t firing. A quiescent neuron’s cross-membrane voltage difference is called its resting membrane potential; it keeps the neuron poised to fire while preventing it from firing at random.

Cortical neurons derived from people with 22q11DS were more excitable, the study found. This is likely because of their abnormal resting membrane potential, Pasca said. The 22q11DS-derived neurons spontaneously fired four times as frequently as neurons derived from people in the control group. This altered resting membrane potential also led to abnormalities in calcium signaling in the 22q11DS neurons. Treating these neurons with any of three different antipsychotic drugs effectively reversed the defects in resting membrane potential and calcium signaling, and prevented these neurons from being so excitable.

The researchers also studied a gene called DGCR8, which has been suspected of being tied to schizophrenia. DGCR8 is one of scores of genes normally residing along a stretch of chromosomal DNA that’s deleted in a person with 22q11DS.

Knocking down DGCR8’s activity levels in the control neurons reproduced the weakened resting membrane potential and associated malfunctions seen in the 22q11DS neurons. Boosting the activity of the gene through genetic manipulation or by applying antipsychotic drugs to 22q11DS neurons largely restored that potential.

“DGCR8 is probably the main player in the cellular defects we observed,” Pasca said. Some of these defects are probably also present in some other forms of schizophrenia, he added.

“We can’t test hallucinations in a dish,” Pasca said. “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.”

There are undoubtedly many types of schizophrenia, he said. “But clinically, 22q11DS-related schizophrenia isn’t very different from other forms of schizophrenia. Some of the mechanisms we’ve identified here may turn out to apply to those more genetically or environmentally complex types of schizophrenia.”

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Pasca is a member of Stanford Bio-X, the Stanford Maternal & Child Health Research Institute, and Stanford Wu Tsai Neurosciences Institute, and is a faculty fellow of Stanford ChEM-H.

Other Stanford co-authors of the study are former medical student Anna Krawisz, MD; former postdoctoral scholars Carleton Goold, PhD, Yishan Sun, PhD, and Masayuki Yazawa, PhD; former undergraduate student Julia Schaepe; former visiting researcher Kazuya Ikeda, MD; postdoctoral medical fellow Neal Amin, MD, PhD; postdoctoral scholar Min-Yin Li, PhD; basic life research scientist Noriaki Sakai, DVM, PhD; Seiji Nishino, MD, PhD, professor emeritus of psychiatry and behavioral sciences; Matthew Porteus, MD, professor of pediatrics; Jonathan Bernstein, MD, associate professor of pediatrics; Ruth O’Hara, PhD, professor of psychiatry and behavioral sciences; Joachim Hallmayer, MD, professor of psychiatry and behavioral sciences; and John Huguenard, PhD, professor of neurology.

Researchers at UCLA; Yonsei University College of Medicine in Seoul, South Korea; the National Institute of Mental Health; and the Novartis Institutes for Medical Research also contributed to the study.

The work was funded by the National Institutes of Health (grants R01MH107800, R01MH100900, R01MH085953, R37MH060233 and R01MH094714); the Behavioral and Brain Research Foundation; the New York Stem Cell Foundation; the MQ Foundation; the Stanford Wu Tsai Neurosciences Institute’s Brain Rejuvenation Project; the Stanford Human Brain Organogenesis Program; the Uytengsu Family Research Fund; the Kwan Research Fund; the California Institute for Regenerative Medicine; the National Research Foundation of Korea; the National Science Foundation; the Feldman Gift Fund; the Maternal and Child Health Research Institute; the Autism Science Foundation; a Stanford Medicine Dean’s Fellowship; the Howard Hughes Medical Institute; Stanford Bio-X; and the Ministry of Science, ICT & Future Planning in Korea.

The Stanford University School of Medicine consistently ranks among the nation’s top medical schools, integrating research, medical education, patient care and community service. For more news about the school, please visit http://med.stanford.edu/school.html. The medical school is part of Stanford Medicine, which includes Stanford Health Care and Stanford Children’s Health. For information about all three, please visit http://med.stanford.edu.

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Bruce Goldman
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