Prenatal lead exposure and schizophrenia: a plausible neurobiologic connection.

In their article in the April issue of EHP, Opler et al. (2004) raise the intriguing possibility that prenatal exposure to the ubiquitous developmental neurotoxicant lead ([Pb.sup.2+]) may be associated with schizophrenia, an adult psychiatric disease. Although the study has certain limitations that the authors discussed, it brings to light the possibility that prenatal [Pb.sup.2+] exposure may be a risk factor for the expression of schizophrenia later in life. If an association between developmental [Pb.sup.2+] exposure and schizophrenia exists, then identifying plausible neurobiologic substrate(s) would be useful in future studies. A common and potentially critical link between developmental [Pb.sup.2+] exposure and schizophrenia is the disruption of glutamatergic synaptic activity--specifically, hypoactivity of the N-methyl-D-aspartate subtype (NMDAR) of glutamatergic receptors.

The "glutamatergic hypothesis" of schizophrenia originated from observations that administration of NMDAR noncompetitive antagonists exacerbates psychotic symptoms in schizophrenics and mimics schizophrenia in nonpsychotic subjects (Coyle et al. 2003; Konradi and Heckers 2003). Further, the administration of such antagonists in animals models certain aspects of the disease. There is experimental evidence that [Pb.sup.2+] is a potent and selective inhibitor of the NMDAR, and the NMDAR plays an important role in neuronal development, synaptic plasticity, and learning and memory (Nihei and Guilarte 2001). Similar to rats exposed to [Pb.sup.2+] during development, several lines of evidence have implicated NMDAR hypofunction in the pathophysiology of schizophrenia (Coyle et al. 2003; Konradi and Heckers 2003).

Developmental exposure to Pb2+, in the same concentration range as implied in the work by Opler et al. (2004), alters gene and protein expression of NMDAR subunits in the rat brain (Nihei and Guilarte 2001). A consistent change in NMDAR subunits measured in young adult [Pb.sup.2+]-exposed rats is a decrease in NR1 subunit gene expression (Nihei and Guilarte 2001). These findings resemble some of the changes in NMDAR subunit expression described in the brain of schizophrenic patients (Konradi and Heckers 2003; Tsai and Coyle 2002). Further, there is compelling evidence for a common molecular target, the glycine modulatory site of the NMDAR. A proposed mechanism by which [Pb.sup.2+] inhibits NMDAR function is by binding to a divalent cation site associated with the glycine site and allosterically inhibiting glycine binding (Hashemzadeh-Gargari and Guilarte 1999). The significance of the antagonistic action of [Pb.sup.2+] at the glycine site of the NMDAR is that studies have identified abnormalities associated with schizophrenia that interfere with the activation of the glycine modulatory site of the NMDAR (Coyle and Tsai 2004a). Further, the use of NMDAR glycine site agonists such as glycine, D-serine, or D-cycloserine in clinical trials has demonstrated some efficacy in ameliorating the negative symptoms and cognitive disabilities in schizophrenics (Coyle and Tsai 2004a, 2004b).

Although an environmental component to the etiology of schizophrenia has been proposed (Tsuang 2000), developmental [Pb.sup.2+] exposure has not been considered a potential risk factor for schizophrenia until the article by Opler et al. (2004) was published. It is possible that in susceptible individuals, the presence of [Pb.sup.2+] during the development of the central nervous system may be directly related or may contribute to the expression of schizophrenia later in life.

The work on [Pb.sup.2+] and the NMDAR is supported by grant ES06189 from the National Institute of Environmental Health Sciences.

The author declares he has no competing financial interests.

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.

REFERENCES

Coyle JT, Tsai G, 2004a. The NMDA receptor glycine modulatory site: a therapeutic target for improving cognition and reducing negative symptoms in schizophrenia. Psychopharmacology 174:32-38.

Coyle JT, Tsai G. 2004b, NMDA receptor function, neuroplasticity, and the pathophysiology of schizophenia. Int Rev Neurobiol 59:491-515.

Coyle JT, Tsai G, Goff D. 2003. Converging evidence of NMOA receptor hypofunction in the pathophysiology of schizophrenia. Ann NY Acad Sci 1003:318-327.

Hashemzadeh-Gargari H, Guilarte TR. 1999. Divalent cations modulate N-methyl-D-aspartare receptor function at the glycine site. J Pharm Exp Ther 290:1356-1362.

Konradi C, Heckers S. 2003. Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment. Pharmacol Ther 97:153-179.

Nihei MK, Guilarte TR. 2001. Molecular changes in glutamatergic synapses induced by [Pb.sup.2+]: association with deficits of LTP and spatial learning. Neurotoxicology 22:635-643.

Opler MGA, Brown AS, Graziano J, Desai M, Zheng W, Schaefer C, et al. 2004. Prenatal lead exposure, [delta]-aminolevulinic acid, and schizophrenia. Environ Health Perspect 112:548-552.

Tsai G, Coyle JT. 2002. Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 42:165-179.

Tsuang M. 2000. Schizophrenia: genes and environment. Biol Psychiatry 47:210-220.

Tomas R. Guilarte

Department of Environmental

Health Sciences

The Johns Hopkins University 

Bloomberg School of Public Health

Baltimore, Maryland

E-mail: [e-mail]