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Schizophr Bull. 2014 May;40(3):575-84. doi: 10.1093/schbul/sbt071. Epub 2013 May 28.

Chronic exposure of mutant DISC1 mice to lead produces sex-dependent abnormalities consistent with schizophrenia and related mental disorders: a gene-environment interaction study.

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1
*To whom correspondence should be addressed; Department of Environmental Health Sciences, Columbia University, Mailman School of Public Health, 722 West 168th Street, Room 1105-E, New York, NY 10032, US; tel: 212-305-3959, fax: 212-305-3857, e-mail: trguilarte@columbia.edu.

Abstract

The glutamatergic hypothesis of schizophrenia suggests that hypoactivity of the N-methyl-D-aspartate receptor (NMDAR) is an important factor in the pathophysiology of schizophrenia and related mental disorders. The environmental neurotoxicant, lead (Pb(2+)), is a potent and selective antagonist of the NMDAR. Recent human studies have suggested an association between prenatal Pb(2+) exposure and the increased likelihood of schizophrenia later in life, possibly via interacting with genetic risk factors. In order to test this hypothesis, we examined the neurobehavioral consequences of interaction between Pb(2+) exposure and mutant disrupted in schizophrenia 1 (mDISC1), a risk factor for major psychiatric disorders. Mutant DISC1 and control mice born by the same dams were raised and maintained on a regular diet or a diet containing moderate levels of Pb(2+). Chronic, lifelong exposure of mDISC1 mice to Pb(2+) was not associated with gross developmental abnormalities but produced sex-dependent hyperactivity, exaggerated responses to the NMDAR antagonist, MK-801, mildly impaired prepulse inhibition of the acoustic startle, and enlarged lateral ventricles. Together, these findings support the hypothesis that environmental toxins could contribute to the pathogenesis of mental disease in susceptible individuals.

KEYWORDS:

DISC1; MRI; NMDA receptor; Pb2+exposure; gene-environment interaction; schizophrenia

PMID:
23716713
PMCID:
PMC3984515
DOI:
10.1093/schbul/sbt071
[Indexed for MEDLINE]
Free PMC Article

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