Mechanisms of divalent metal toxicity in affective disorders

Abstract

Metals are required for proper brain development and play an important role in a number of neurobiological functions. The divalent metal transporter 1 (DMT1) is a major metal transporter involved in the absorption and metabolism of several essential metals like iron and manganese. However, non-essential divalent metals are also transported through this transporter. Therefore, altered expression of DMT1 can modify the absorption of toxic metals and metal-induced toxicity. An accumulating body of evidence has suggested that increased metal stores in the brain are associated with elevated oxidative stress promoted by the ability of metals to catalyze redox reactions, resulting in abnormal neurobehavioral function and the progression of neurodegenerative diseases. Metal overload has also been implicated in impaired emotional behavior, although the underlying mechanisms are not well understood with limited information. The current review focuses on psychiatric dysfunction associated with imbalanced metabolism of metals that are transported by DMT1. The investigations with respect to the toxic effects of metal overload on behavior and their underlying mechanisms of toxicity could provide several new therapeutic targets to treat metal-associated affective disorders.

Keywords: Cadmium; Divalent metal transporter 1; Emotion; Iron; Lead; Manganese.

Figure 1. Potential mechanisms of brain metal overload in the development of affective disorders and neurodegenerative diseases

Various factors alter components of metal metabolism, thereby influencing metal status in the body and brain. Brain metal overload causes neurodegeneration and neurotransmitter dysfunction by inducing oxidative stress. Reactive oxygen species (ROS) impair various components of neurotransmitter pathways, which ultimately manifests as psychiatric/affective disorders.