Wiring Anomalies in the Fetal Brain Due To a Faulty Protein May Be a Causal Factor in Schizophrenia

Wiring Anomalies in the Fetal Brain Due To a Faulty Protein May Be a Causal Factor in Schizophrenia

Posted: January 20, 2015

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New research from a team at Rutgers University sheds new light on brain biology and pathology that contributes to schizophrenia. The work was led by Bonnie L. Firestein, Ph.D., a recipient of two NARSAD grants, most recently a Distinguished Investigator award in 2012.

Dr. Firestein and her colleagues focused their research on a gene that past studies have shown to be mutated in some people with schizophrenia. The gene, called NOS1AP, holds the DNA code that tells cells how to manufacture a protein, also called NOS1AP. The team wanted to identify the role of NOS1AP in the wiring-up of the brain very early on in development. After neurons are born they have to migrate to regions of the brain where they ultimately take up residence and connect with neighboring neurons. As reported online October 29th in Biological Psychiatry, the team observed this process in embryonic rats, whose brains are structurally similar to human brains in many important respects.

In some of the animals, the researchers experimentally overexpressed the NOS1AP protein; in others, they prevented its expression. Too much of the protein disrupted the normal neural migration process, resulting in too many young nerve cells taking up residence in one part of the cortex and too few in another. (The cortex is the seat of higher brain function.) Postmortem studies of people with schizophrenia have indicated the presence of cortical wiring abnormalities. Interestingly, the scientists noted that pathology in the animals with too much of the NOS1AP protein resembled the pathology that occurs when the NMDA receptor is inhibited. This receptor is an important brain “docking port” and some scientists have suggested that under-active NMDA receptors are a cause of schizophrenia symptoms.

Dr. Firestein’s team, which included two-time NARSAD grantee Linda M. Brzustowicz, M.D., also found that when they prevented NOS1AP from being manufactured in cells, migration of neurons in the cortex increased abnormally. This increased migration interfered with the pattern that enables cortical cells to properly assemble into circuits. Specific abnormalities were found in the formation of dendrites, the branching structures that neurons sprout to connect with other neurons.

The research shows that problems in the initial wiring-up of the brain cause abnormalities seen in the brains of patients with schizophrenia and likely may be a causal factor in disease. The scientists note that because degrees of pathology vary from person to person, it is possible that such wiring abnormalities may not cause schizophrenia, but rather predispose an individual to develop symptoms in the presence of other factors such as adverse environmental factors.

Read the abstract.