Mini-Brain Research Supports Move to Molecular Psychiatry

Oct 1, 2020 | CNS, Genetic, Neurology, News, Schizophrenia

Mini-Brain Research Supports Move to Molecular Psychiatry

On September 28 the Stanford Medicine News Center published a look at the nerve cells that can mark schizophrenia. When not firing, nerve cells are “supposed to keep quiet.” When they start, “popping off at random” it can obscure the intended signals. In the most common genetic schizophrenia, “it seems that the nerve cells won’t shut up, Stanford University School of Medicine have found. And they think they know why.” One out of 3,000 folks carry the genetic defect known as, “22q11.2 deletion syndrome, or 22q11DS.” One of the most common chromosome deletions known in humans, people with this defect have a 30-fold risk for schizophrenia, “dwarfing the magnitude of all other known genetic or environmental risk factors.” Also, around 35% of people with this deletion are diagnosed with autism spectrum early in life. Till now, no one knew why this deletion has such a profound effect on mental health.

New Tech May Allow New Age in Psychiatry

The experiments published September 28 in Nature Medicine may have located, “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.” And one gene seems to be the key to this, “electrical abnormality.” Sergiu Pasca, professor of psychiatry and behavioral science, “envisions defining…psychiatric diseases in terms of their molecular underpinnings — what he calls molecular psychiatry.” The phrase seeks to differentiate itself from traditional symptom-centered psychiatric practices. “Oncologists can learn a lot about the underlying drivers of a patient’s cancer by studying a tumor biopsy,” Pasca opined. “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.” Yet new technology, “circumvents that difficulty.” He went on, “We’ve been working from behavior down—-Here, we’re working from molecules up.”

Brains in a Jar

Several years ago, Pasca developed “cortical spheroids” which are round, “clusters of brain cells in a dish.” They are made from skin cells and grown, “for months or even years in a dish.” Once grown, they are made of both neurons and other key brain cells, recapitulating, “some of the architecture of the human cerebral cortex, a brain region often associated with schizophrenia symptoms.” The scientists made these “mini-brains” from 15 22q11S carriers and 15 non-carriers. Turning to regular brains, “even asymptomatic 22q11DS carriers remain at elevated risk of developing schizophrenia throughout their lifetimes.” Neurons have a “resting membrane potential,” the cross-membrane difference in voltage. This keeps them, “poise to fire while preventing [them] from firing at random.” The neurons made from the 22q11DS carriers showed a lower voltage difference from the inside to the outside of the cell membrane, hence less “potential.” 

Antipsychotics Help “Schizophrenic” Mini-Brains Function More Normally

These neurons were also “more excitable” likely due to the abnormal resting  membrane potential, and they were four times more likely to spontaneously fire compared to the control group. Importantly, “antipsychotic drugs effectively reversed the defects in resting membrane potential and calcium signaling, and prevented neurons from being so excitable.” They also looked at gene DGCR8, one suspected of a link to schizophrenia. This gene is normally deleted in those with 22q11DS. Reducing DGCR8’s activity led to the same lessened resting membrane potential, “and associated malfunction seen in the 22g11DS neurons.” But increases in DGC8’s activity via, “genetic manipulation or by applying antipsychotic drugs to 22q11DS neurons largely restored that potential.” Pasca opined, “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.”

The lead authors of this study are Pasca, of the Stanford Brain Organogenesis Program; Stanford grad student Themasap Khan; post-doc scholar Omer Revah; and Aaron Goron who is a postdoc scholar at UCLA. Pasca is the co-organizer of the Inaugural Cold Spring Harbor Meeting on Human Brain Development and 3D Modeling, as well as the Co-director of the Cold Spring Harbor Course in Autism Spectrum Disorders.

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