Rat Study Finds Lead has Detrimental Effect on Cells in Brain Areas Implicated in Schizophrenia

A study of the brains of rats exposed to lead has uncovered striking similarities with what is known about the brains of human schizophrenia patients, adding compelling evidence that lead is a factor in the onset of schizophrenia.

Results of the study by scientists at Columbia University’s Mailman School of Public Health appear in the journal Translational Psychiatry.

The researchers found that lead had a detrimental effect on cells in three brain areas implicated in schizophrenia: the medial prefrontal cortex, the hippocampus, and the striatum of rats exposed to lead before birth and in the early part of their lives. Density of brain cells known as Parvalbumin-Positive GABAergic interneurons, or PVGI, declined by approximately a third–at roughly the same percentage decline seen in schizophrenia patients. And, using imaging technology, they identified higher levels of a dopamine receptor called D2R. Again, the magnitude of the increase matched what has been documented in human schizophrenia patients, and in a previous study of genetically engineered mice.

“The similarities in the brain structure and neuronal systems between what we see in lead-exposed rats and human schizophrenia patients is striking, and adds to a growing body of literature suggesting that early lead exposure primes the brain for schizophrenia later in life,” says senior author Tomás Guilarte, PhD, chair of Environmental Health Sciences at the Mailman School.

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This is a photo of a rat brain.
The detrimental effect of lead exposure was seen in cells in the medial prefrontal cortex, hipocampus and striatum of the rats. This image is for illustrative purposes only. Image credit: S. B. Raymond et al./PLOS ONE.

Cocaine Insights

In a related finding, the researchers found that rats exposed to lead had a much stronger reaction to cocaine than healthy rat controls. In the experiment, lead-exposed rats that were injected with cocaine ran around in their cages at twice the distance of lead-free control rats. The rat behavior is meaningful because it mirrors what is seen in schizophrenia patients, who are known to have a heightened response to the drug.

Schizophrenia is not the only possible consequence of lead exposure. A follow-up experiment will allow the rats to self-administer cocaine in order to test whether lead exposure plays a role in addiction.

“We are currently assessing the impact of lead exposure on both the rewarding and reinforcing properties of addictive drugs like cocaine while exploring the biological underpinnings of how lead exposure plays a role in addiction,” says first author Kirstie Stansfield, PhD, associate research scientist at the Mailman School.

About this schizophrenia research

Additional authors of the current study include Kristen N. Ruby, Barbara Soares, Jennifer L. McGlothan, and Xinhua Liu–all of Columbia’s Mailman School of Public Health. The research was supported by grants from the National Institute of Environmental Health Sciences (ES006189, ES020465, and P30ES009089).

Contact: Tim Paul – Columbia University
Source: Columbia University press release
Image Source: The image is credited to S. B. Raymond et al./PLOS ONE and is licensed Creative Commons Attribution 2.5 Generic
Original Research: Full open access research for “Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia” by K H Stansfield, K N Ruby, B D Soares, J L McGlothan, X Liu and T R Guilarte in Translational Psychiatry. Published online March 10 2015 doi:10.1038/tp.2014.147

Open Access Neuroscience Abstract

Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia

Environmental factors have been associated with psychiatric disorders and recent epidemiological studies suggest an association between prenatal lead (Pb2+) exposure and schizophrenia (SZ). Pb2+ is a potent antagonist of the N-methyl-d-aspartate receptor (NMDAR) and converging evidence indicates that NMDAR hypofunction has a key role in the pathophysiology of SZ. The glutamatergic hypothesis of SZ posits that NMDAR hypofunction results in the loss of parvalbumin (PV)-positive GABAergic interneurons (PVGI) in the brain. Loss of PVGI inhibitory control to pyramidal cells alters the excitatory drive to midbrain dopamine neurons increasing subcortical dopaminergic activity. We hypothesized that if Pb2+ exposure in early life is an environmental risk factor for SZ, it should recapitulate the loss of PVGI and reproduce subcortical dopaminergic hyperactivity. We report that on postnatal day 50 (PN50), adolescence rats chronically exposed to Pb2+ from gestation through adolescence exhibit loss of PVGI in SZ-relevant brain regions. PV and glutamic acid decarboxylase 67 kDa (GAD67) protein were significantly decreased in Pb2+ exposed rats with no apparent change in calretinin or calbindin protein levels suggesting a selective effect on the PV phenotype of GABAergic interneurons. We also show that Pb2+ animals exhibit a heightened locomotor response to cocaine and express significantly higher levels of dopamine metabolites and D2-dopamine receptors relative to controls indicative of subcortical dopaminergic hyperactivity. Our results show that developmental Pb2+ exposure reproduces specific neuropathology and functional dopamine system changes present in SZ. We propose that exposure to environmental toxins that produce NMDAR hypofunction during critical periods of brain development may contribute significantly to the etiology of mental disorders.

“Early-life lead exposure recapitulates the selective loss of parvalbumin-positive GABAergic interneurons and subcortical dopamine system hyperactivity present in schizophrenia” by K H Stansfield, K N Ruby, B D Soares, J L McGlothan, X Liu and T R Guilarte in Translational Psychiatry. Published online March 10 2015 doi:10.1038/tp.2014.147.

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