The Quantum Dots Neurotoxicity And The Underlying Mechanisms

As a class of nanomaterials with unique optical and electrical properties,quantum dots(QDs) are now being widely applied in biology and medicine.However,the prevalence of these man-made nanomaterials increases the likelihood of exposure to environment and organism,which brings the potential following risks.In this paper, in a rat primary hippocampal culture model and the hippocampal DG area of Wistar rats,we explored the biocompatibility and biosafety of QDs and the underlying mechanisms using whole-cell patch clamp,calcium imaging,immunohistochemistry, western blotting,dendrite(spine) morphology and in vivo field potential recordings techniques.Results:(1) Effects of QDs on intracellular calcium homeostasis in primary cultured hippocampal neuronsWe found that QDs could elevate internal calcium levels([Ca²⁺]_i) for long in a dose-dependent manner.10 nM and above unmodified CdSe QDs could induce [Ca²⁺]_i rise for at least 15 minutes.[Ca²⁺]_i rise couldn't be totally blocked when calcium-free external solutions or pre-incubation of thapsigargin(used for depletion of calcium in calcium stores) were used.These indicate that external calcium could influx into the cell and internal calcium could be released from calcium stores under QD exposure.Furthermore,the external calcium was found to influx mainly through N-type calcium channels and voltage-gated sodium channels.Meantime,the internal source was more complex.Sodium ions influx through voltage-gated sodium channels could trigger mitochondrial sodium-calcium exchangers(MNCX),then,some calcium ions could be pumped out from the mitochondrion.These calcium ions and those from external further activated ryanodine receptors in endoplasmic reticulum(ER) followed by much more calcium release from ER,which might be the process known as calcium induced calcium release.Our results showed that QD might interfere with internal calcium homeostasis and the following risks should be noticed,otherwise, these effects should be considered when tracking receptors or proteins with QDs.(2) Effects of QDs on voltage-gated sodium channels(VGSCs)Given that VGSCs play a central role in QD-induced[Ca²⁺]_i rise,we examined the effects of QDs on VGSCs employing the conventional whole-cell patch clamp.We explored the changes of the functional properties of activation,inactivation and recovery of sodium currents under QD insult for 24 hours.The results showed that 10 nM and above unmodified CdSe QDs could cause the curve of activation to a depolarized way,while they prolonged the activation course.Meantime,they shifted the curve of inactivation to a hyperpolarized direction,slowed the recovery of sodium channels and reduced the fraction of available sodium channels.These ambivalent results imply the diversity and complexity of QD toxicology.(3) QDs enhance synaptie transmission but impair synaptic plasticity in the hippocampal dentate gyrus area of anethetized rats in vivoConsidering that both[Ca²⁺]_i and VGSCs could interfere with synaptic transmission and plasticity,we then used in vivo field potential recordings to explore the effects of QDs(unmodified CdSe QDs and well modified strep-CdSe/ZnS QDs) on synaptic transmission and plasticity in the hippocampal DG area of anethetized rats.These results show that both of the two kinds of QDs could enhance the basal synaptic transmission,boosting the basal fEPSP slope and PS amplitude and the IO functions, while they could impair the short- and long-term potentiation,suppressing the paired-pulses reactions and Ion.g-term potentiation.And these two kinds of QDs showed comparative impairment on the synaptic transmission and plasticity.These results imply that we must eliminate or reduce QD in vivo toxicity before any further clinical use.