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.

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

Fig. 1.

Pb²⁺ exposure produced elevated locomotor activity in open field. (A) Central activity in control (control) and mutant disrupted in schizophrenia 1 (mDISC1) (mutant) male mice raised on regular (regular) or Pb²⁺ (lead) diet; *P < .05 vs control mice. (B) Peripheral activity in control (control) and mDISC1 (mutant) male mice raised on regular (regular) or Pb²⁺ (lead) diet; *P < .05 vs mice of the same genotype but raised on regular food. (C) Rearing activity in control (control) and mDISC1 (mutant) male mice raised on regular (regular) or Pb²⁺ (lead) diet; *P < .05 vs mice of the same genotype but raised on regular food. (D) Central activity in control (control) and mDISC1 (mutant) female mice raised on regular (regular) or Pb²⁺ (lead) diet; *P < .05 vs control mice. (E) Peripheral activity in control (control) and mDISC1 (mutant) female mice raised on regular (regular) or Pb²⁺ (lead) diet; *P < .05 vs the control regular group. (F) Rearing activity in control (control) and mDISC1 (mutant) female mice raised on regular (regular) or Pb²⁺ (lead) diet; *P < .05 vs the mutant regular group. n = 10 in each group.

Fig. 2.

Chronic Pb²⁺ exposure increases anxiety levels in control and mDISC1 mice. (A) Decreased time spent in open arms in control and mDISC1 male mice exposed to Pb²⁺ (lead) compared with regular diet (regular), n = 10 mice per group; *P < .05 vs mice of the same genotype but raised on regular food. (B) Decreased time spent in open arms in control and mDISC1 female mice exposed to Pb²⁺ (lead) compared with regular diet (regular), n = 10 mice per group; *P < .05 vs mice of the same genotype but raised on regular food; Y axes: OT, open arm time; TT, total arms time.

Fig. 3.

DISC1 mutant mice exposed to Pb²⁺ exhibit greater responses to the N-methyl-d-aspartate (NMDA) antagonist, MK-801. (A) Locomotor activity in open field of male mice before and after treatment with MK-801 (0.3mg/kg, intraperitoneally). Compared with control male mice raised on regular diet, mutant male mice display significantly greater activity in response to MK-801. Compared with mutant male mice raised on regular diet, mutant mice exposed to Pb²⁺ diet also exhibit greater response to the stimulant during the first 20 min after injection; *P < .05 vs mice of all other groups; n = 5 mice per group. (B) Locomotor activity in open field of female mice before and after treatment with MK-801 (0.3mg/kg, intraperitoneally). Compared with control female mice raised on regular diet, mutant female mice display significantly greater activity in response to MK-801. Compared with mutant female mice raised on regular diet, mutant female mice exposed to Pb²⁺ show significantly greater response to the stimulant during the last 25 min of the observational period following injection; *P < .05 vs mice of all other groups; n = 5 mice per group; arrows point to the time of injection.

Fig. 4.

Reduced prepulse inhibition (PPI) is rescued by d-serine in mDISC1 female mice exposed to Pb²⁺. (A) PPI in saline-treated control (control) and mDISC1 (mutant) male mice fed regular (regular) or Pb²⁺ (lead) diet; prepulses are as follows—open bar: 4 dB; dotted bar: 8 dB; horizontal lines bar: 12 dB; right slash lines bar: 16 dB; filled bar: 20 dB. (B) PPI in d-serine-treated (2.7g/kg, intraperitoneally) control (control) and mDISC1 (mutant) male mice raised on regular (regular) or Pb²⁺ (lead) diet. (C) PPI in saline-treated control (control) and mDISC1 (mutant) female mice raised on regular (regular) or Pb²⁺ (lead) diet; prepulses are as follows—open bar: 4 dB; dotted bar: 8 dB; horizontal lines bar: 12 dB; right slash lines bar: 16 dB; filled bar: 20 dB; *P < .05 vs the same prepulse intensity in all other groups of mice. (D) PPI in d-serine-treated (2.7g/kg, intraperitoneally) control (control) and mDISC1 (mutant) female mice raised on regular (regular) or Pb²⁺ (lead) diet. n = 8–10 mice per group.

Fig. 5.

Brain volume effects of gene-environment interaction. (A) Representative MRI 3D images for the control-regular, control-lead, mutant-regular, and mutant-lead groups of female mice. The lateral ventricles are outlined in purple. (B) No genotype- or diet-related alterations in lateral ventricle volume in male mice. (C) mDISC1 female mice exposed to Pb²⁺ had a marked increase in lateral ventricle volume compared with all other groups; *P = .05 for the genotype × diet interaction; n = 5 mice per group.