Dr. Sergiu Pasca

Stanford scientists link problems in nerve cells to schizophrenia

/ Yimy Villa / Leave a comment
A spherical cluster of hundreds of thousands of brain cells cultured in a lab dish. A team of researchers studied such neuronal clusters to better understand schizophrenia.
Image Credit: Pasca lab

The neurological origins of mental illness continue to remain a mystery and along with it any potential treatments for these conditions. However, Dr. Sergiu Pasca and his team at Stanford University have come one step closer to unlocking these mysteries for schizophrenia, a mental disorder characterized by disruptions in thought processes, perceptions, emotional responsiveness, and social interactions. 

A common genetic defect called 22q11.2 deletion syndrome, or 22q11DS for short, has been linked to an astonishing 30-fold increased risk for developing schizophrenia. With help from CIRM funding, Dr. Pasca and his team have linked this genetic defect to an electrical defect in nerve cells.

To look at this more closely, the Stanford team generated tiny clusters of brain cells, called cortical spheroids which contain brain nerve cells, in a dish using skin cells from 22q11DS carriers and those from normal patients. The team then measured the resting membrane potential of these nerve cells, which is the voltage difference between the inner and outer part of the cell. This measurement is important because it keeps the nerve cells ready to fire while also preventing them from firing at random.

Dr. Pasca and his team found abnormal levels of resting membrane potential in nerve cells in the cortical spheroids made from 22q11DS carriers. They also found that the the 22q11DS-derived nerve cells spontaneously fired four times as frequently as nerve cells derived from normal patients. What’s even more promising is that the team found that treating the 22q11DS-derived nerve cells with any of three different antipsychotic drugs effectively reversed the defects in resting membrane potential and helped in prevent spontaneous firing.

Dr. Sergiu Pasca

In a press release, Dr. Pasca elaborated more on the team’s findings.

“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 full results of this study were published in Nature Medicine.

3D brain model shows potential for treatment of hypoxic brain injuries in infants

/ Yimy Villa / Leave a comment
Image of 3D brain cultures in the Sergiu Pasca lab.
Photo courtesy of Timothy Archibald.

A baby’s time in the womb is one of the most crucial periods in terms of its development. The average length of gestation, which is defined as the amount of time in the womb from conception to birth, is approximately 40 weeks. Unfortunately, for reasons not yet fully understood, there are times that babies are born prematurely, which can lead to problems.

These infants can have underdeveloped portions of the brain, such as the cerebral cortex, which is responsible for advanced brain functions, including cognition, speech, and the processing of sensory and motor information. The brains of premature infants can be so underdeveloped that they are unable to control breathing. This, in combination with underdeveloped lungs, can lower oxygen levels in the blood, which can lead to hypoxic, or low oxygen related, brain injuries.

In a previous study, doctors Anca and Sergiu Pasca and their colleagues at Stanford developed a technique to create a 3D brain that mimics structural and functional aspects of the developing human brain.

Using this same technique, in a new study with the aid of CIRM funding, the team grew a 3D brain that contained cells and genes similar to the human brain midway through the gestational period. They then exposed this 3D brain to low oxygen levels for 48 hours, restored the oxygen level after this time period, and observed any changes.

It was found that progenitor cells in a region known as the subventricular zone, a region that is critical in the growth of the human cortex, are affected. Progenitor cells are “stem cell like” cells that give rise to mature brain cells such as neurons. They also found that the progenitor cells transitioned from “growth” mode to “survival” mode, causing them to turn into neurons sooner than normal, which leads to fewer neurons in the brain and underdevelopment.

In a press release, Dr. Anca Pasca is quoted as saying,

“In the past 20 years, we’ve made a lot of progress in keeping extremely premature babies alive, but 70% to 80% of them have poor neurodevelopmental outcomes.”

The team then tested a small molecule to see if it could potentially reverse this response to low oxygen levels by keeping the progenitor cells in “growth” mode. The results of this are promising and Dr. Sergiu Pasca is quoted as saying,

“It’s exciting because our findings tell us that pharmacologically manipulating this pathway could interfere with hypoxic injury to the brain, and potentially help with preventing damage.”

The complete findings of this study were published in Nature.