Methylmercury: a potential environmental risk factor contributing to epileptogenesis

Abstract

Epilepsy or seizure disorder is one of the most common neurological diseases in humans. Although genetic mutations in ion channels and receptors and some other risk factors such as brain injury are linked to epileptogenesis, the underlying cause for the majority of epilepsy cases remains unknown. Gene-environment interactions are thought to play a critical role in the etiology of epilepsy. Exposure to environmental chemicals is an important risk factor. Methylmercury (MeHg) is a prominent environmental neurotoxicant, which targets primarily the central nervous system (CNS). Patients or animals with acute or chronic MeHg poisoning often display epileptic seizures or show increased susceptibility to seizures, suggesting that MeHg exposure may be associated with epileptogenesis. This mini-review highlights the effects of MeHg exposure, especially developmental exposure, on the susceptibility of humans and animals to seizures, and discusses the potential role of low level MeHg exposure in epileptogenesis. This review also proposes that a preferential effect of MeHg on the inhibitory GABAergic system, leading to disinhibition of excitatory glutamatergic function, may be one of the potential mechanisms underlying MeHg-induced changes in seizure susceptibility.

Figure 1

Schematic diagram of a potential mechanism underlying MeHg-induced changes in neuronal excitability. Under normal conditions, neuronal excitability in the mammalian brains is maintained by well-balanced glutamatergic excitatory and GABAergic inhibitory synaptic activities (Top). Following MeHg exposure, on one hand, MeHg preferentially affects GABAergic inhibitory function result in disinhibition of glutamatergic excitatory function, leading to increased release of neurotransmitter from presynaptic terminals. On the other hand, MeHg also directly stimulates release of glutamate from presynaptic terminals, selectively inhibits glutamate uptake by astrocytes and stimulates glial release of glutamate. These actions will result in an increased extracellular glutamate concentration. Thus, the consequence of the combined effects of MeHg on GABAergic and glutamatergic systems will lead to unbalanced neuronal excitability toward to hyperexcitability direction (Bottom). Abbreviations: GABA, gamma-amino butyric acid; Glu, glutamate; GAD, glutamic acid decarboxylase; EAAT, excitatory amino acid transporters.