Cornel University researchers recently made a breakthrough in the study on schizophrenia with human-derived cerebral organoids.
Schizophrenia is a chronic brain disorder of hitherto unknown etiology, with typical symptoms usually appearing in early adulthood and affecting approximately 1% of the global population. Clinically, schizophrenia often presents as a syndrome with varying symptoms involving multiple impairments in perception, thinking, emotion, and behavior, as well as incoordination of mental activities. Patients are generally conscious and have essentially normal intelligence, although some may experience impairment of cognitive function during the course of the disease.
There are indications that schizophrenia begins at an early developmental stage, even as risk begins to accumulate in the womb. Since ethically obtaining tissue from the developing human brain is an impossible task, for decades, the timeline for the onset of schizophrenia-related pathology remained only speculative.
Previous epidemiological evidence suggests that prenatal stress and starvation, early vitamin D deficiency, and a weak maternal immune system may all increase the risk of schizophrenia.
A team of researchers from Cornell University discovered that the risk of schizophrenia can be detected as early as the first three months of brain development by studying human-derived “mini-brains”, in a recent study published in Molecular Psychiatry. The research fills a knowledge gap about schizophrenia.
Symptoms typically arise in adulthood. However, researchers have discovered significant changes in the ventricles and cortex of patients’ brains in previous autopsy investigations. These disparities, they believe, may emerge early in life.
Researchers employed 21 induced pluripotent stem cells (iPSCs) from schizophrenia patients and healthy volunteers to develop mature 3D brain organoids (mini-brains) to evaluate neuropathology during this crucial period, which encapsulate the transcriptome and epigenome of fetal development and roughly mimic the first three months of human brain development.
The researchers discovered two genes crucial to brain development that were lowered using single-cell RNA sequencing to evaluate gene expression in 21 organoids: a gene expression regulator called BRN2 and a pleiotropic growth factor (PTN). The early development of the brain was altered as a result of their diminished expression, which also resulted in greater brain cell death.
The researchers discovered that replacing the missing BRN2 in the organoid restored brain cell function. Adding more PTN helped cut down brain cell death levels. They believe that if subsequent research confirm the association, it will lead to the development of a new gene therapy to treat brain cell disorders.
The mini-brains were also utilized to investigate the involvement of various cell types in the development of schizophrenia. Endothelial cells, which line blood arteries and emit immune chemicals known as cytokines, were the focus of this experiment. Researchers discovered that during early growth, the mini-brain had a high number of endothelial cells, which can contribute to an exaggerated inflammatory response to infection. This could explain the association between maternal infection during pregnancy and schizophrenia in mice, according to the researchers.
The study’s first author, Dr. Michael Notaras, said, “this study, we believe, is the first in human tissue to show that various cell-specific processes exist and may play a role in schizophrenia risk. It forces us to rethink when the disease really begins and how we should think about developing the next generation schizophrenia treatments.”
The technique could also be used to study the early pathology of late-onset neuropsychiatric or neurodegenerative diseases such as Alzheimer’s disease or Huntington’s disease, according to the researchers.