Although schizophrenia and other psychiatric disorders are known to have genetic origins, environmental factors, too, are relevant. One such factor is prenatal bleeding, specifically, fetal cerebral hemorrhage. Close examination of this factor suggests that schizophrenia can be triggered by a molecule, lysophosphatidic acid (LPA).

The molecule is produced during hemorrhaging, and it has been linked to developmental processes that are believed to increase the risk of psychiatric disorders. Extending these findings, researchers from The Scripps Research Institute (TSRI) have now shown that LPA can cause schizophrenia-like symptoms in animal models. These researchers have indicated that LPA not only changes behavior, but also alters brain chemistry and gene expression.

The new results appeared April 7 in the journal Translational Psychiatry, in an article entitled, “LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage.” The article hints at new approaches that could help prevent or treat psychiatric disorders such as schizophrenia, bipolar disorder, and autism.

To evaluate the effects of increased LPA signaling, the TSRI scientists developed a model of fetal cerebral hemorrhage in which fetal mice received an injection of a nonreactive saline solution, blood serum (which naturally contains LPA in addition to other molecules), or pure LPA. Then, ten weeks after the mice were born, they were tested for schizophrenia-like symptoms.

“This model exhibits behavioral, neurochemical, and schizophrenia-related gene expression alterations in adult females,” the authors wrote. “Behavioral alterations in amphetamine-induced locomotion, prepulse inhibition, thigmotaxis and social interaction—in addition to increases in tyrosine hydroxylase-positive dopaminergic cells in the substantia nigra and ventral tegmental area and decreases in parvalbumin-positive cells in the prefrontal cortex—were induced upon prenatal serum exposure.”

After they conducted global gene expression studies, the researchers found that both prenatal serum and LPA exposure altered the expression of many genes and pathways related to schizophrenia, including the expression of Grin2b, Slc17a7, and Grid1.

To further test the role of LPA, the researchers used a molecule to block only LPA signaling in the brain. This treatment prevented schizophrenia-like symptoms.

“This new model speaks to how schizophrenia could arise before birth and identifies possible novel drug targets,” said Jerold Chun, M.D., Ph.D., a professor and member of the Dorris Neuroscience Center at TSRI and senior author of the study.

Besides pointing to potential therapies, the study also raises new questions into the developmental origins of psychiatric disorders. For example, the researchers only saw symptoms in female mice. Could schizophrenia be triggered by different factors in men and women as well?

“Hopefully this animal model can be further explored to tease out potential differences in the pathological triggers that lead to disease symptoms in males versus females,” said Elizabeth A. Thomas, Ph.D., an associate professor at TSRI and co-author of the study.

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