Prenatal Lead Exposure and Schizophrenia: Further Evidence and More Neurobiological Connections
Environ Health Perspect. doi:10.1289/ehp.0800484 available via http://dx.doi.org [Online 28 April 2009]
Referencing: Prenatal Exposure to Lead, δ-Aminolevulinic Acid, and Schizophrenia: Further Evidence
In 2004, Opler et al. published a study in Environmental Health Perspectives (EHP) suggesting an association between prenatal lead (Pb2+) exposure and schizophrenia (Opler et al. 2004). In the November 2008 issue of EHP, Opler et al. (2008) further supported this association using a different cohort of subjects. In a letter published in EHP in 2004 (Guilarte 2004), I indicated that a plausible neurobiological connection between prenatal Pb2+ exposure and schizophrenia may be that Pb2+ is a potent antagonist of the N-methyl-d-aspartate (NMDA) receptor (NMDAR), and NMDAR hypofunction is thought to be involved in the pathophysiology of the disease. Since then, another plausible neurobiological connection has surfaced, and this relates to hippocampal neurogenesis. Neurogenesis occurs not only during development but is also prominent in the adult brain (Laplagne et al. 2006). A well-characterized neurogenic zone in the adult brain is the subgranular zone of the dentate gyrus (DG) in the hippocampus (Zhao et al. 2008). Although the significance of newly born neurons in the adult hippocampus is currently under investigation, the overwhelming evidence supports a role in hippocampus-dependent learning (Dupret et al. 2008; Imayoshi et al. 2008).
Schizophrenia patients express cognitive deficits that may be related to hippocampal dysfunction (Gothelf et al. 2000; Sweatt 2004). So, what is the new neurobiological connection between Pb2+ exposure and schizophrenia? Recent evidence indicates that neurogenesis is decreased in schizophrenia patients, and this decrease may contribute to their cognitive dysfunction (Kempermann et al. 2008; Reif et al. 2006). In an animal model using the NMDAR antagonist phencyclidine (PCP) to induce schizophrenia-like symptoms in mice, Maeda et al. (2007) observed reduced DG neurogenesis that was reversed by the atypical antipsychotic drug clozapine. Co-administration of d-serine and glycine also inhibited the PCP-induced decrease in neurogenesis. PCP, like Pb2+, is an NMDAR antagonist, and D-serine and glycine activate NMDAR; this suggests that chronic NMDAR hypofunction decreases neurogenesis in the hippocampus, an observation consistent with my comments in 2004 (Guilarte 2004). Models of developmental Pb2+ exposure have also shown decreased DG neurogenesis and are associated with deficits in learning (Jaako-Movits et al. 2005; Verina et al. 2007). Therefore, reduced DG neurogenesis appears to be a common factor in schizophrenia and in animal models of schizophrenia and developmental Pb2+ exposure.
Schizophrenia is a neurodevelopmental disorder that is expressed later in life. Pb2+ is a neurotoxicant that is known to cause developmental abnormalities. Animal models of developmental Pb2+ exposure express a behavioral phenotype with features that overlap with those in animal models of schizophrenia, including increased spontaneous activity, decreased social interaction, and learning deficits (Moreira et al. 2001; Nihei et al. 2000). Also, some of the behavioral effects described in adolescents with early-life Pb2+ exposure are similar to those expressed in schizophrenia patients (Opler and Susser 2005). Thus, although the environmental causes of schizophrenia have not evaluated environmental toxicants, the emerging evidence from the human studies by Opler and colleagues and animal studies suggest that prenatal Pb2+ exposure may be an environmental risk factor for schizophrenia.
The author declares he has no competing financial interests.
Tomás R. Guilarte
Environmental Health Sciences
Johns Hopkins Bloomberg School of Public Health
Baltimore, Maryland
E-mail: tguilart@jhsph.edu
References
Dupret D, Revest J-M, Koehl M, Ichas F, De Giorgi F, Costet P, et al. 2008. Spatial relational memory requires hippocampal adult neurogenesis. PloS One 3(4): e1959; doi:10.1371/journal.pone.0001959 [Online 9 April 2008].
Gothelf D, Soreni N, Nachman RP, Tyano S, Hiss Y, Reiner O, et al. 2000. Evidence for the involvement of the hippocampus in the pathophysiology of schizophrenia. Eur Neuropsychopharmacol 10:389–395.
Guilarte TR. 2004. Prenatal lead exposure and schizophrenia: a plausible neurobiologic connection [Letter]. Environ Health Perspect 112:A724.
Imayoshi I, Sakamoto M, Ohtsuka T, Takao K, Miyakawa T, Yamaguchi M, et al. 2008. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat Neurosci 11:1153–1161.
Jaako-Movits K, Zharkovsky T, Romantchick O, Jurgenson M, Merisalu E, Heidmets L-T, et al. 2005. Developmental lead exposure impairs contextual fear conditioning and reduces adult hippocampal neurogenesis in the rat brain. Int J Devl Neurosci 23:627–635.
Kempermann G, Krebs J, Fabel K. 2008. The contribution of failing adult hippocampal neurogenesis to psychiatric disorders. Curr Opin Psychiatry 21:290–295.
Laplagne DA, Esposito MS, Piatti VC, Morgenstern NA, Zhao C, van Praag H, et al. 2006. Functional convergence of neurons generated in the developing and adult hippocampus. PloS Biol 4(12): e409; doi: 10.1371/journal.pbio.0040409 [Online 21 November 2006].
Maeda K, Sugino H, Hirose T, Kitagawa H, Nagai T, Mizoguchi H, et al. 2007. Clozapine prevents decrease in neurogenesis in mice repeatedly treated with phencyclidine. J Pharmacol Sci 103:299–308.
Moreira EG, Vassilieff I, Vassilieff VS. 2001. Developmental lead exposure: behavioral alterations in the short and long term. Neurotoxicol Teratol 23:489–495.
Nihei MK, Desmond NL, McGlothan JL, Kuhlmann AC, Guilarte TR. 2000. N-Methyl-d-aspartate receptor subunit changes are associated with Pb2+-induced deficits of long-term potentiation and spatial learning. Neurosci 99:233–242.
Opler MGA, Brown AS, Graziano J, Desai M, Zheng W, Schaefer C, et al. 2004. Prenatal lead exposure, δ-aminolevulinic acid, and schizophrenia. Environ Health Perspect 112:548–552.
Opler MGA, Buka SL, Groeger J, McKeague I, Wei C, Factor-Litvak P, et al. 2008. Prenatal exposure to lead, δ-aminolevulinic acid, and schizophrenia: further evidence. Environ Health Perspect 116:1586–1590.
Opler MGA, Susser ES. 2005. Fetal environment and schizophrenia. Environ Health Perspect 113:1239–1242.
Reif A, Fritzen S, Finger M, Strobel A, Lauer M, Schmitt A, et al. 2006. Neural stem cell proliferation is decreased in schizophrenia, but not in depression. Mol Psychiatry 11:514–522.
Sweatt JD. 2004. Hippocampal function in cognition. Psychopharmacol 174:99–110.
Verina T, Rohde CA, Guilarte TR. 2007. Environmental lead exposure during early life alters granule cell neurogenesis and morphology in the hippocampus of young adult rats. Neuroscience 145:1037–1047.
Zhao C, Deng W, Gage FH. 2008. Mechanisms and functional implications of adult neurogenesis. Cell 132:645–660.
Editor’s note: In accordance with journal policy, Opler et al. were asked whether they wanted to respond to this letter, but they chose not to do so.