Abstract
BackgroundMercury is a well-known neurotoxin implicated in a wide range of neurological or psychiatric disorders including autism spectrum disorders, Alzheimer’s disease, Parkinson’s disease, epilepsy, depression, mood disorders and tremor. Mercury-induced neuronal degeneration is thought to invoke glutamate-mediated excitotoxicity, however, the underlying mechanisms remain poorly understood. Here, we examine the effects of various mercury concentrations (including pathological levels present in human plasma or cerebrospinal fluid) on cultured, rat cortical neurons.ResultsWe found that inorganic mercuric chloride (HgCl2 –at 0.025 to 25 μM) not only caused neuronal degeneration but also perturbed neuronal excitability. Whole-cell patch-clamp recordings of pyramidal neurons revealed that HgCl2 not only enhanced the amplitude and frequency of synaptic, inward currents, but also increased spontaneous synaptic potentials followed by sustained membrane depolarization. HgCl2 also triggered sustained, 2–5 fold rises in intracellular calcium concentration ([Ca2+]i). The observed increases in neuronal activity and [Ca2+]i were substantially reduced by the application of MK 801, a non-competitive antagonist of N-Methyl-D-Aspartate (NMDA) receptors. Importantly, our study further shows that a pre incubation or co-application of MK 801 prevents HgCl2-induced reduction of cell viability and a disruption of β-tubulin.ConclusionsCollectively, our data show that HgCl2-induced toxic effects on central neurons are triggered by an over-activation of NMDA receptors, leading to cytoskeleton instability.
Highlights
Mercury is a well-known neurotoxin implicated in a wide range of neurological or psychiatric disorders including autism spectrum disorders, Alzheimer’s disease, Parkinson’s disease, epilepsy, depression, mood disorders and tremor
Several studies have revealed that mercury levels in brain tissues are 2–10 fold higher in patients with dental amalgam fillings, Alzheimer’s disease, autism spectrum disorders, epilepsy or hydrocephalus [35,36,37,38]
Based on the fact that HgCl2 used at 25 μM consistently caused neuronal damage to both developing and more mature neurons during short-term and long-term exposure, we investigated the mechanisms underlying the toxic effect of HgCl2 on cortical neurons using the concentration of 25 μM in all subsequent experiments, unless stated otherwise
Summary
Mercury is a well-known neurotoxin implicated in a wide range of neurological or psychiatric disorders including autism spectrum disorders, Alzheimer’s disease, Parkinson’s disease, epilepsy, depression, mood disorders and tremor. Mercury has been shown to affect several aspects of glutamatergic signaling, including the inhibition of glutamate reuptake in astrocyte [23], inhibition of glutamine synthetase activity [24], and an enhancement of spontaneous glutamate release from neurons [25]. These effects result in an increase in glutamate concentration at the synaptic cleft. The mercury-induced toxic effects on the nervous tissue have been well documented, the findings are often conflicting and the underlying mechanisms remain poorly defined
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