Why 22q11 Deletion Syndrome Raises Schizophrenia Risk 30X


One out of every 3,000 people carries a genetic defect known as 22q11.2 deletion syndrome, or 22q11DS. It is one of the most widespread chromosomal deletions known to occur in humans. People carrying 22q11DS are at a 30-times higher risk for schizophrenia than those in the general population. This dwarfs the magnitude of all other known genetic or environmental risk factors. Additionally, some 30%-40% of individuals with this deletion receive a diagnosis of autism spectrum disorder early in their lives.

Why does this genetic variation so gravely raise the risk for these conditions? Until now, an understanding of the reasons remained elusive.

New experiments1 have now identified a change in an electrical property of cortical neurons in carriers of the deletion. The alteration could explain how people develop schizophrenia, which is characterized by hallucinations, delusions, and cognitive decline.

The researchers pinpointed a single gene that appears to be largely responsible for the electrical abnormality.

Instead of describing psychiatric disorders as collections of behavioral symptoms, senior author Sergiu Pasca, associate professor of psychiatry and behavioral sciences at Stanford University, 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. 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. We’ve been working from behavior down. Here, we’re working from molecules up,

Pasca says.

Cerebral Cortical Organoids

To uncover the electrical defect in neurons, researchers generated and manipulated tiny spherical organoids of brain cells in a dish. Each clustered organoid contained hundreds of thousands of cells. Pasca first developed these so-called cortical spheroids, composed of neurons and other important brain cells, several years ago.

Sourced 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.

Pasca and colleagues used skin cells taken from 15 different 22q11DS carriers and 15 healthy control subjects to create cortical spheroids. Not all of the 22q11DS donors had manifested schizophrenia’s hallmark symptoms. Although schizophrenia usually reveals itself in late adolescence or early adulthood, even asymptomatic 22q11DS carriers remain at elevated risk of developing schizophrenia throughout their lifetimes.

Abnormal Voltage

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 researchers found. This is likely because of their abnormal resting membrane potential, Pasca says.

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.

Knocking Out DGCR8

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.

Pasca says that DGCR8 is probably the main player in the cellular defects the researchers have observed. Some of these defects are probably also present in some other forms of schizophrenia.

We can’t test hallucinations in a dish. 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,

Pasca says. There are undoubtedly many types of schizophrenia.

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,

he adds.

  1. Khan, T.A., Revah, O., Gordon, A. et al. Neuronal defects in a human cellular model of 22q11.2 deletion syndrome. Nat Med (2020). https://doi.org/10.1038/s41591-020-1043-9 ↩︎


Last Updated on October 15, 2022