Researchers in a Johns Hopkins Children’s Center-led study that used genetic material from human blood and lab-grown brain cells say they have made progress in developing a blood test to identify disease-associated changes in the brain specifically linked to postpartum depression and other psychiatric and neurological disorders.
The research findings, published January 11 in Molecular Psychiatry, focused on identifying the “footprints” of brain cell-derived mRNAs in blood circulating outside the brain. These blood extracellular vesicles carry brain-specific pieces of genetic material that potentially allow researchers to detect disease-associated changes in gene activity inside the brain.
The new research was inspired, investigators say, by results of a study published in September 2022, in which Johns Hopkins Medicine scientists discovered EV communication is altered in pregnant women who go on to develop postpartum depression after giving birth.
First, using the human placenta as a model, the investigators identified 26 placental mRNAs that are present in maternal blood only during pregnancy and not following birth, proving that mRNAs from specific tissues are found in EVs in circulating blood. Then, using lab-grown human brain tissue derived from stem cells (brain organoids), researchers found that EV mRNAs that are released from these brain tissues reflected the changes occurring inside the tissues. Sarven Sabunciyan, Ph.D., and his team conclude that it is possible to gather biological information about normally inaccessible tissues, such as the placenta and the brain, by examining EV mRNAs circulating in blood.
They were able to identify mRNAs that are specifically expressed in the brain using data from the Human Protein Atlas — a Swedish-based database of human proteins in cells, tissues and organs — and the Genotype-Tissue Expression Project, which has extensively cataloged mRNA levels in human tissues.
Further analysis of those mRNA genetic pathways showed that the brain-specific mRNAs in blood EVs were involved in particular brain functions, and were significantly enriched for genes already associated with brain disorders that involve mood, schizophrenia, epilepsy and substance abuse.
The research team says this analysis suggests that these mRNAs are likely to be ideal biological markers for identifying such conditions.
Researchers also discovered 13 brain-specific mRNAs in the blood that were found to be associated with postpartum depression. To determine the extent to which blood EV mRNAs reflect transcription in the brain, researchers compared mRNAs isolated from cells and EVs in a brain organoid model. They found that although cellular and extracellular mRNA levels are not identical, they do correlate, and it is possible to extrapolate cellular expression changes in the brain via EV mRNA levels.
