title: Chronic exposure of mutant DISC1 mice to lead produces sex-dependent abnormalities consistent with schizophrenia and related mental disorders: a gene-environment interaction study.
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.
authors.affiliation: *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.
authors.forename: Bagrat
authors.initials: B
authors.lastname: Abazyan
authors.forename: Jenifer
authors.initials: J
authors.lastname: Dziedzic
authors.forename: Kegang
authors.initials: K
authors.lastname: Hua
authors.forename: Sofya
authors.initials: S
authors.lastname: Abazyan
authors.forename: Chunxia
authors.initials: C
authors.lastname: Yang
authors.forename: Susumu
authors.initials: S
authors.lastname: Mori
authors.forename: Mikhail V
authors.initials: MV
authors.lastname: Pletnikov
authors.forename: Tomas R
authors.initials: TR
authors.lastname: Guilarte
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002552:Cerebral Ventricles / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D059647:Gene-Environment Interaction; D007854:Lead / Q000494:pharmacology*; D007855:Lead Poisoning / Q000150:complications*; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics*; D065808:Prepulse Inhibition / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012021:Reflex, Abnormal / Q000187:drug effects; D013216:Reflex, Startle / Q000187:drug effects; D012559:Schizophrenia / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D012737:Sex Factors
chemical_list: C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D007854:Lead
keywords: DISC1; MRI; NMDA receptor; Pb2+exposure; gene-environment interaction; schizophrenia