Acute Enhancement of Synaptic Transmission and Chronic Inhibition of Synaptogenesis Induced by Perfluorooctane Sulfonate through Mediation of Voltage-Dependent Calcium Channel

Abstract

Perfluorooctane sulfonate (PFOS) is a persistent and bioaccumulative pollutant ubiquitous in wildlife and humans. Although the distribution and fate of PFOS have been widely studied, its potential neurotoxicity remains largely unknown. In the present study, the acute and chronic effects of PFOS on the development and synaptic transmission of hippocampal neurons was examined. Perfusion with PFOS markedly increased the frequency of miniature postsynaptic currents (mPSCs) and slightly elevated the amplitude of mPSCs in cultured hippocampal neurons. Perfusion with PFOS also increased the amplitude of field excitatory postsynaptic potentials (fEPSPs) recorded in the CA1 region of hippocampal slices. Both of these effects were largely blocked by the L-type Ca 2+ channel antagonist nifedipine. Further studies showed that PFOS enhanced inward Ca 2+ currents and increased intracellular Ca 2+ in cultured neurons; these effects were also substantially inhibited by nifedipine. Moreover, prolonged treatment with PFOS moderately inhibited neurite growth and dramatically suppressed synaptogenesis in cultured neurons in a nifedipine-sensitive manner. Thus, through enhancement of Ca 2+ channels, PFOS may exhibit both acute excitotoxic effects on synaptic function and chronically inhibit synaptogenesis in the brain.

Effects of perfluorooctane sulfonate on ion channels and glutamate-activated current in cultured rat hippocampal neurons

“…In the previous work (Liao et al, 2008), we revealed that acute perfusion of PFOS (10 M and above) rapidly enhanced synaptic activity in both cultured hippocampal neurons and hippocampal brain slices, while chronic treatment with PFOS (50 M) moderately inhibited neurite outgrowth and dramatically suppressed synaptogenesis in cultured neurons. We further showed that PFOS (10 M and above) enhanced inward Ca 2+ currents and increased intracellular Ca 2+ in neurons through enhancement of L-type Ca 2+ channels, a mechanism that may underlie PFOS' acute effects on synaptic transmission and chronic action on neuronal development.…”

“…In contrast, NMDA receptors gate much more slowly, desensitize only weakly, are highly Ca 2+ -permeable and are blocked by extracellular Mg 2+ in a strongly voltage-dependent manner (Wollmuth and Sobolevsky, 2004). Our previous work exhibited that PFOS not only increased the amplitude but also left-ward shifted the I-V curves of Ca 2+ currents in cultured hippocampal neurons (Liao et al, 2008). The present work shows that PFOS slightly elevate the K + currents and alter the steady-state activation of Na + currents toward the hyperpolarized direction.…”

Perfluorooctane Sulfonate Induces Apoptosis in N9 Microglial Cell Line

“…Recent studies reported that PFOS may exhibit both acute excitotoxic effects on synaptic function and chronically inhibit synaptogenesis in the brain through enhancement of Ca 2þ channels in cultured rat hippocampal neurons, which revealed the damage of this pollutant to nerve system. 29 Microglia are now firmly established as key cellular elements in the CNS, and they are recognized to serve as the brain's innate immune system. Furthermore, microglia are considered to be a sensitive monitor and can diagnose the integrity of CNS circuity by sensing defunct synapses.…”

Changes in Synaptic Transmission, Calcium Current, and Neurite Growth by Perfluorinated Compounds Are Dependent on the Chain Length and Functional Group

“…Despite the hydrophilic nature of their sulfonyl or carboxyl head groups, PFOS and PFOA can cross the cell membrane and enter the developing brain possibly because of either their surfactant properties or the immaturity of the fetal/neonatal blood-brain barrier (5,26). An in vitro study on cultured rat hippocampal neurons showed that through enhancement of Ca 2+ channels, PFOS may exhibit both acute excitotoxic effects on synaptic function and may chronically inhibit synaptogenesis in the brain (30). Recent evidence indicated that PFCs show signs of a variety of toxicological effects to organisms, such as those mentioned previously, and the effects appear to differ with their carbon chain length (5,31).…”