Lead acts to trigger schizophrenia
Mice engineered with a human gene for schizophrenia and exposed to lead during early life exhibited behaviors and structural changes in their brains consistent with schizophrenia. Scientists at Columbia University’s Mailman School of Public Health and the Johns Hopkins University School of Medicine say their findings suggest a synergistic effect between lead exposure and a genetic risk factor, and open an avenue to better understanding the complex gene-environment interactions that put people at risk for schizophrenia and other mental disorders.
Results appear online in Schizophrenia Bulletin.
Going back to 2004, work by scientists at the Mailman School 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? Based on his own research, Tomas R. Guilarte, PhD, senior author of the new study, 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. His 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, professor and chair of the department of Environmental Health Sciences at the Mailman School, and his co-investigators 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,” says Dr. Guilarte. “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,” adds Dr. Guilarte, noting that DISC1 is among many implicated in schizophrenia.
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. One ongoing study by Dr. Guilarte is looking at whether lead exposure alone can contribute to deficits of one specialized type of neuron called parvalbumin-positive GABAergic interneuron that is known to be affected in the brain of schizophrenia patients. Scientists are also interested to establish the critical window for exposure - whether in utero or postnatal, or both.
Scientists have long known that schizophrenia runs in families. The illness occurs in 1 percent of the general population, but it occurs in 10 percent of people who have a first-degree relative with the disorder, such as a parent, brother, or sister. People who have second-degree relatives (aunts, uncles, grandparents, or cousins) with the disease also develop schizophrenia more often than the general population. The risk is highest for an identical twin of a person with schizophrenia. He or she has a 40 to 65 percent chance of developing the disorder.
We inherit our genes from both parents. Scientists believe several genes are associated with an increased risk of schizophrenia, but that no gene causes the disease by itself. In fact, recent research has found that people with schizophrenia tend to have higher rates of rare genetic mutations. These genetic differences involve hundreds of different genes and probably disrupt brain development.
Other recent studies suggest that schizophrenia may result in part when a certain gene that is key to making important brain chemicals malfunctions. This problem may affect the part of the brain involved in developing higher functioning skills. Research into this gene is ongoing, so it is not yet possible to use the genetic information to predict who will develop the disease.
Despite this, tests that scan a person’s genes can be bought without a prescription or a health professional’s advice. Ads for the tests suggest that with a saliva sample, a company can determine if a client is at risk for developing specific diseases, including schizophrenia. However, scientists don’t yet know all of the gene variations that contribute to schizophrenia. Those that are known raise the risk only by very small amounts. Therefore, these “genome scans” are unlikely to provide a complete picture of a person’s risk for developing a mental disorder like schizophrenia.
In addition, it probably takes more than genes to cause the disorder. Scientists think interactions between genes and the environment are necessary for schizophrenia to develop. Many environmental factors may be involved, such as exposure to viruses or malnutrition before birth, problems during birth, and other not yet known psychosocial factors.
Scientists are learning more about brain chemistry and its link to schizophrenia.
“The animal model provides a way forward to answer important questions about the physiological processes underlying schizophrenia,” says Dr. Guilarte.
The principal active ingredient in marijuana causes transient schizophrenia-like symptoms ranging from suspiciousness and delusions to impairments in memory and attention, according to a Yale research study.
Lead author D. Cyril D’Souza, M.D., associate professor of psychiatry at Yale School of Medicine, said the study was an attempt to clarify a long known association between cannabis and psychosis in the hopes of finding another clue about the pathophysiology of schizophrenia.
“Just as studies with amphetamines and ketamine advanced the notion that brain systems utilizing the chemical messengers dopamine and NMDA receptors may be involved in the pathophysiology in schizophrenia, this study provides some tantalizing support for the hypotheses that the brain receptor system that cannabis acts on may be involved in the pathophysiology of schizophrenia,” he said. “Clearly, further work is needed to test this hypothesis.”
D’Souza and his co-researchers administered various doses of delta-9-THC, the main active ingredient in cannabis, to subjects who were screened for any vulnerability to schizophrenia. Some subjects developed symptoms resembling those of schizophrenia that lasted approximately one half hour to one hour.
These symptoms included suspiciousness, unusual thoughts, paranoia, thought disorder, blunted affect, reduced spontaneity, reduced interaction with the interviewer, and problems with memory and attention. THC also induced euphoria and increased levels of the stress hormone cortisol. There were no side effects in the study participants one, three and six months after the study.
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The study’s first author is Bagrat Abazyan, MD, a post-doctoral fellow in the Behavioral Neurobiology and Neuroimmunology Lab, Department of Psychiatry and Behavioral Sciences at Johns Hopkins School of Medicine, which is led by Mikhail Pletnikov, MD, PhD, senior co-author of the paper and principal developer of the DISC1 mouse model. Neuroimaging studies were led by Susumu Mori, PhD, Department of Radiology, also of Johns Hopkins.
Funding for the study was provided by the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health to Dr. Guilarte, principal investigator of grant #ES006189 and a Virtual Consortium for Translational/Transdisciplinary Environmental Research (ViCTER) supplement to #ES006189.
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Timothy S. Paul
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Columbia University’s Mailman School of Public Health