Manganese neurotoxicity and glutamate-GABA interaction

Abstract

Brain extracellular concentrations of amino acids (e.g. aspartate, glutamate, taurine) and divalent metals (e.g. zinc, copper, manganese) are primarily regulated by astrocytes. Adequate glutamate homeostasis is essential for the normal functioning of the central nervous system (CNS). Glutamate is of central importance for nitrogen metabolism and, along with aspartate, is the primary mediator of the excitatory pathways in the brain. Similarly, the maintenance of proper manganese levels is important for normal brain functioning. Several in vivo and in vitro studies have linked increased manganese concentrations with alterations in the content and metabolism of neurotransmitters, namely dopamine, γ-aminobutyric acid, and glutamate. It has been reported by our laboratory and others, that cultured rat primary astrocytes exposed to manganese displayed decreased glutamate uptake, thereby increasing the excitotoxic potential of glutamate. Furthermore, decreased uptake of glutamate has been associated with decreased gene expression of glutamate:aspartate transporter (GLAST) in manganese-exposed astroctyes. Additional studies have suggested that attenuation of astrocytic glutamate uptake by manganese may be a consequence of reactive oxygen species (ROS) generation. Collectively, these data suggest that excitotoxicity may occur due to manganese-induced altered glutamate metabolism, representing a proximate mechanism for manganese-induced neurotoxicity.

Introduction

Manganese (Mn) is an essential trace element that is found in varying amounts in all tissues. Manganese concentrations are highest in tissues rich in mitochondria, where it forms stable complexes with ATP and inorganic phosphate. Manganese functions as a constituent of metalloenzymes and an activator of enzymes. For example, arginase, a manganese containing enzyme, is essential in urea formation; pyruvate carboxylase, the rate-limiting enzyme in gluconeogenesis, and the antioxidant, manganese superoxide dismutase (MnSOD), also utilize manganese as a constituent (Hurley and Keen, 1987). While rare in occurrence, manganese deficiency in humans has been reported, and it is characterized with skeletal abnormalities and seizure activity, probably due to decreased MnSOD and glutamine synthetase (GS) activities (Critchfield et al., 1993). Exposure to excessive manganese is more widely reported (see below for conditions) and it is associated with psychological and motor disturbances (Calne et al., 1994, Pal et al., 1999).

Symptoms of chronic manganese neurotoxicity (manganism) are similar to those associated with Parkinson’s Disease (PD); however, clinically they are distinct. Similarities between PD and manganism include the presence of generalized bradykinesia and widespread rigidity. Dissimilarities between PD and manganism include (1) a less frequent resting tremor, (2) more frequent dystonia, (3) a particular propensity to fall backwards, (4) failure to detect a reduction in fluorodopa uptake by positron emission tomography (PET; Calne et al., 1994, Pal et al., 1999) in manganism. Given these clinical differences, it has been proposed that manganese neurotoxicity does not directly damage the nigrostriatal pathway, as in PD, but causes PD-like effects by damaging output pathways downstream from the nigrostriatal dopaminergic pathway (see Fig. 1A; Calne et al., 1994, Pal et al., 1999, Verity, 1999). Manganism is linked with increased brain levels of manganese, primarily in those brain regions known to be iron-rich, namely, caudate putamen, globus pallidus, substantia nigra, and subthalamic nuclei. These regions are collectively referred to as the basal ganglia.

Glutamate is the most prevalent excitatory neurotransmitter (Cotman et al., 1981), whereas γ-aminobutyric acid (GABA) is the most abundant inhibitory neurotransmitter (Olsen and DeLorey, 1999). Cortical glutamate afferents project into the striatum where, in concert with GABA and dopamine, motor behaviors are controlled (Carlsson and Carlsson, 1990). Glutamate is converted to GABA by decarboxylation via glutamate decarboxylase (GAD) and is degraded via GABA-transaminase. Altered glutamatergic and GABAergic functioning can contribute to altered striatal dopamine metabolism (Page et al., 2001, Castro and Zigmond, 2001). Therefore, we have postulated that the neurotoxic effects of manganese on striatal dopamine may be indirectly mediated via abnormal striatal glutamate and/or GABA metabolism, and that temporally, changes in areas that are known to avidly accumulate manganese precede the well described effects of manganese on dopaminergic function. Specifically, it is hypothesized that manganese accumulation in the globus pallidus causes decreased GABAergic efferent firing from the globus pallidus into the subthalamic nuclei. Consequently, glutamatergic projections into the substantia nigra that originate from the subthalamic nuclei, will fire in an uncontrolled manner causing dysregulation of dopaminergic output into the striatum from the substantia nigra (see Fig. 1B). This review will discuss some of the latest studies that focus on manganese-induced alterations of glutamate neurochemistry.