Oxidative stress has been suggested to contribute to the pathophysiology of schizophrenia. In particular, oxidative damage to lipids, proteins, and DNA as observed in schizophrenia is known to impair cell viability and function, which may subsequently account for the deteriorating course of the illness. Currently available evidence points towards an alteration in the activities of enzymatic and nonenzymatic antioxidant systems in schizophrenia. In fact, experimental models have demonstrated that oxidative stress induces behavioural and molecular anomalies strikingly similar to those observed in schizophrenia. These findings suggest that oxidative stress is intimately linked to a variety of pathophysiological processes, such as inflammation, oligodendrocyte abnormalities, mitochondrial dysfunction, hypoactive N-methyl-D-aspartate receptors and the impairment of fast-spiking gamma-aminobutyric acid interneurons.[BKYB1] Such self-sustaining mechanisms may progressively worsen producing the functional and structural consequences associated with schizophrenia. Recent clinical studies have shown antioxidant treatment to be effective in ameliorating schizophrenic symptoms. Hence, identifying viable therapeutic strategies to tackle oxidative stress and the resulting physiological disturbances provide an exciting opportunity for the treatment and ultimately prevention of schizophrenia.

Based on the human epidemiological association between prenatal infection and higher risk of schizophrenia, a number of animal models have been established to explore the long-term brain and behavioral consequences of prenatal immune challenge. Accumulating evidence suggests that the vulnerability to specific forms of schizophrenia-related abnormalities is critically influenced by the precise timing of the prenatal immunological insult. In the present study, we tested the hypothesis whether late prenatal immune challenge in mice may induce long-term behavioral and neurochemical dysfunctions primarily associated with the negative symptoms of schizophrenia. We found that prenatal exposure to the viral mimic polyriboinosinic-polyribocytidilic acid (Poly-I:C; 5 mg/kg, i.v.) on gestation day (GD) 17 led to significant deficits in social interaction, anhedonic behavior, and alterations in the locomotor and stereotyped behavioral responses to acute apomorphine (APO) treatment in both male and female offspring. In addition, male but not female offspring born to immune challenged mothers displayed behavioral/cognitive inflexibility as indexed by the presence of an abnormally enhanced latent inhibition (LI) effect. Prenatal immune activation in late gestation also led to numerous, partly sex-specific changes in basal neurotransmitter levels, including reduced dopamine (DA) and glutamate contents in the prefrontal cortex and hippocampus, as well as reduced γ-aminobutyric acid (GABA) and glycine contents in the hippocampus and prefrontal cortex, respectively. The constellation of behavioral and neurochemical abnormalities emerging after late prenatal Poly-I:C exposure in mice leads us to conclude that this immune-based experimental model provides a powerful neurodevelopmental animal model especially for (but not limited to) the negative symptoms of schizophrenia.

Zinc is a life-sustaining trace element, serving structural, catalytic, and regulatory roles in cellular biology. It is required for normal mammalian brain development and physiology, such that deficiency or excess of zinc has been shown to contribute to alterations in behavior, abnormal central nervous system development, and neurological disease. In this light, it is not surprising that zinc ions have now been shown to play a role in the neuromodulation of synaptic transmission as well as in cortical plasticity. Zinc is stored in specific synaptic vesicles by a class of glutamatergic or "gluzinergic" neurons and is released in an activity-dependent manner. Because gluzinergic neurons are found almost exclusively in the cerebral cortex and limbic structures, zinc may be critical for normal cognitive and emotional functioning. Conversely, direct evidence shows that zinc might be a relatively potent neurotoxin. Neuronal injury secondary to in vivo zinc mobilization and release occurs in several neurological disorders such as Alzheimer's disease and amyotrophic lateral sclerosis, in addition to epilepsy and ischemia. Thus, zinc homeostasis is integral to normal central nervous system functioning, and in fact its role may be underappreciated. This article provides an overview of zinc neurobiology and reviews the experimental evidence that implicates zinc signals in the pathophysiology of neuropsychiatric diseases. A greater understanding of zinc's role in the central nervous system may therefore allow for the development of therapeutic approaches where aberrant metal homeostasis is implicated in disease pathogenesis.

BackgroundWe have previously reported that the expression of the messenger ribonucleic acid (mRNA) for the NR2A subunit of the N-methyl-D-aspartate (NMDA) class of glutamate receptor was decreased in a subset of inhibitory interneurons in the cerebral cortex in schizophrenia. In this study, we sought to determine whether a deficit in the expression of NR2A mRNA was present in the subset of interneurons that contain the calcium buffer parvalbumin (PV) and whether this deficit was associated with a reduction in glutamatergic inputs in the prefrontal cortex (PFC) in schizophrenia.MethodsWe examined the expression of NR2A mRNA, labeled with a 35S-tagged riboprobe, in neurons that expressed PV mRNA, visualized with a digoxigenin-labeled riboprobe via an immunoperoxidase reaction, in twenty schizophrenia and twenty matched normal control subjects. We also immunohistochemically labeled the glutamatergic axon terminals with an antibody against vGluT1.ResultsThe density of the PV neurons that expressed NR2A mRNA was significantly decreased by 48-50% in layers 3 and 4 in the subjects with schizophrenia, but the cellular expression of NR2A mRNA in the PV neurons that exhibited a detectable level of this transcript was unchanged. In addition, the density of vGluT1-immunoreactive boutons was significantly decreased by 79% in layer 3, but was unchanged in layer 5 of the PFC in schizophrenia.ConclusionThese findings suggest that glutamatergic neurotransmission via NR2A-containing NMDA receptors on PV neurons in the PFC may be deficient in schizophrenia. This may disinhibit the postsynaptic excitatory circuits, contributing to neuronal injury, aberrant information flow and PFC functional deficits in schizophrenia.