Lead Exposure Can Trigger Schizophrenia, Shows Mice Study

In a new study conducted by U.S. team of scientists from Columbia University and the Johns Hopkins University School of Medicine, mice engineered with a human gene for schizophrenia called DISC1 and exposed to lead during early life exhibited behaviors and structural changes in their brains consistent with schizophrenia.

Mutant DISC1 mice exposed to lead and given a psychostimulant exhibited elevated levels of hyperactivity (Westfield State University / Emory University / Sci-News.com)

Mutant DISC1 mice exposed to lead and given a psychostimulant exhibited elevated levels of hyperactivity (Westfield State University / Emory University / Sci-News.com)

Previous studies suggested a connection between prenatal lead exposure in humans and increased risk for schizophrenia later in life. But a big question remained: how could lead trigger the disease?

The scientists led by Dr Tomas Guilarte from the Department of Environmental Health Sciences at Columbia University believed the answer was in the direct inhibitory effect of lead on the N-methyl-D-aspartate receptor (NMDAR), a synaptic connection point important to brain development, learning, and memory. Their research in rodents found that exposure to lead blunted the function of the NMDAR. The glutamate hypothesis of schizophrenia postulates that a deficit in glutamate neurotransmission and specifically hypoactivity of the NMDAR can explain a significant portion of the dysfunction in schizophrenia.

In the new study, Dr Guilarte and colleagues focused on mice engineered to carry the mutant form of Disrupted-in-Schizophrenia-1 (DISC1), a gene that is a risk factor for the disease in humans.

Beginning before birth, half of the mutant DISC1 mice were fed a diet with lead, and half were given a normal diet.

A second group of normal mice not expressing the mutant DISC1 gene were also split into the two feeding groups. All mice were put through a battery of behavioral tests and their brains were examined using MRI.

Mutant mice exposed to lead and given a psychostimulant exhibited elevated levels of hyperactivity and were less able to suppress a startle in response to a loud noise after being given an acoustic warning. Their brains also had markedly larger lateral ventricles – empty spaces containing cerebrospinal fluid – compared with other mice. These results mirror what is known about schizophrenia in humans.

While the role of genes in schizophrenia and mental disorders is well established, the effect of toxic chemicals in the environment is only just beginning to emerge. The study’s results focus on schizophrenia, but implications could be broader.

“We’re just scratching the surface. We used lead in this study, but there are other environmental toxins that disrupt the function of the NMDAR. One of these is a family of chemicals in air pollution called polycyclic aromatic hydrocarbons or PAHs. Similarly, any number of genes could be in play,” said Dr Guilarte, who with colleagues have reported the findings in Schizophrenia Bulletin.

Future research may reveal to what extent schizophrenia is determined by environmental versus genetic factors or their interactions, and what other mental problems might be in the mix.

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Bibliographic information: Bagrat Abazyan et al. Chronic Exposure of Mutant DISC1 Mice to Lead Produces Sex-Dependent Abnormalities Consistent With Schizophrenia and Related Mental Disorders: A Gene-Environment Interaction Study. Schizophr Bull., published online May 28, 2013; doi: 10.1093/schbul/sbt071