The malfunction of neurotransmitter docking ports called NMDA receptors may contribute to schizophrenia in some cases. By chemically blocking these receptors – located on the surface of a class of neurons in the brain –  a team of scientists has mimicked some of the symptoms of the disorder in rats and identified a set of genes whose activity is altered when NMDA receptor activity declines. The study, published October 13 in the journal Translational Psychiatry, points to four human genes that may be involved in schizophrenia.

NARSAD 2006 Independent Investigator Dan Rujescu, M.D., Ph.D., at the University of Halle-Wittenberg, Germany, led the study.

NMDA receptors activate neurons by responding to the neurotransmitter glutamate. Blocking the receptors with drugs or other chemicals has been observed to induce some schizophrenia-like symptoms in both people and animals. One theory proposes that the receptors' activity is inherently low in people with the disorder.

Dr. Rujescu and his team treated rats with low doses of an NMDA receptor-blocking drug, then  measured gene activity in the animals' brain tissue, looking for any genes that were more or less active than they were in untreated animals. They identified 20 such genes. The observed changes in the expression of at least some of these genes could be at least partially responsible for the psychosis-like symptoms that arise when NMDA receptors are blocked, the scientists say.

The team then used what it had learned to help sift through genetic information from people with schizophrenia. Combing through data collected by the international, multi-institution Psychiatric Genomics Consortium from more than 34,000 people with schizophrenia and more than 45,000 healthy controls, the scientists focused their attention on 20 human genes corresponding to the genes that they had identified in their rodent study. Four of these, they concluded, were associated with schizophrenia: SF3B1, FOXP1, DLG2, and VGLL4.  

Further studies will be needed to establish how variations in these genes contribute to schizophrenia. The role of VGLL4 in the brain is unknown, but variations in the other three genes have already been implicated in schizophrenia or other neurodevelopmental disorders. SF3B1 falls within one of 108 genetic locations linked to schizophrenia in a large analysis published last year. Disruptions in DLG2 have also previously been associated with schizophrenia, and mutations affecting FOXP1 have been found in people with intellectual disability, autism, and language impairment.

The team of researchers also included 2015 Young Investigator and 2014 Sidney R. Baer, Jr. Prizewinner Stephan Ripke, M.D.; 2010 Distinguished Investigator and 2014 Lieber Prizewinner Patrick F. Sullivan, M.D.; 1997 Independent Investigator David Andrew Collier, Ph.D.; 2012 Lieber Prizewinner Michael O’Donovan, M.D., Ph.D.; and 2002 Young Investigator and BBRF Scientific Council Member Karoly Mirnics, M.D., Ph.D..

Read the paper.