Long-term maintenance of synaptic plasticity by Fullerenol Ameliorates lead-induced-impaired learning and memory in vivo.

Fullerenol, a functional and water-soluble fullerene derivative, plays an important role in antioxidant, antitumor and antivirus, implying its enormous potential in biomedical applications. However, the in vivo performance of fullerenol remains largely unclear. We aimed to investigate the effect of fullerenol (i.p., 5 mg/kg) on the impaired hippocampus in a rat model of lead exposure. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) is a kind of newly developed soft-ionization mass spectrometry technology. In the present study, an innovative strategy for biological distribution analysis using MALDI-TOF-MS confirmed that fullerenol could across the blood-brain barrier and accumulate in the brain. Results from behavioral tests showed that a low dose of fullerenol could improve the impaired learning and memory induced by lead. Furthermore, electrophysiology examinations indicated that this potential repair effect of fullerenol was mainly due to the long-term changes in hippocampal synaptic plasticity, with enhancement lasting for more than 2-3 h. In addition, morphological observations and biochemistry analyses manifested that the long-term change in synaptic efficacy was accompanied by some structural alteration in synaptic connection. Our study demonstrates the therapeutic feature of fullerenol will be beneficial to the discovery and development as a new drug and lays a solid foundation for further biomedical applications of nanomedicines.

Size-dependent enhancement on conjugative transfer of antibiotic resistance genes by micro/nanoplastics.

Recently micro/nanoplastics (MNPs) have raised intensive concerns due to their possible enhancement effect on the dissemination of antibiotic genes. Unfortunately, data is still lacking to verify the effect. In the study, the influence of polystyrene MNPs on the conjugative gene transfer was studied by using E. coli DH5ɑ with RP4 plasmid as the donor bacteria and E. coli K12 MG1655 as the recipient bacteria. We found that influence of MNPs on gene transfer was size-dependent. Small MNPs (10 nm in radius) caused an increase and then a decrease in gene transfer efficiency with their concentration increasing. Moderate-sized MNPs (50 nm in radius) caused an increase in gene transfer efficiency. Large MNPs (500 nm in radius) had almost no influence on gene transfer. The gene transfer could be further enhanced by optimizing mating time and mating ratio. Scavenging reactive oxygen species (ROS) production did not affect the cell membrane permeability, indicating that the increase in cell membrane permeability was not related to ROS production. The mechanism of the enhanced gene transfer efficiency was attributed to a combined effect of the increased ROS production and the increased cell membrane permeability, which ultimately regulated the expression of corresponding genes.

Electrophysiological phenotypes of synaptic transmission and neural network in hippocampal neurons of the α7-nAChR knockout mice.

It was reported that α7 nicotinic acetylcholine receptor (α7-nAChR) knockout (α7 KO) mice showed few functional phenotypes. The purpose of this study was to investigate the effect of α7 KO on the electrophysiological characteristics of hippocampus in mice. The effect of α7 KO on hippocampal CA3-CA1 synaptic transmission in mice was evaluated by standard extracellular field potential recordings. The electrophysiological phenotype of γ-aminobutyrate A receptors (GABAA-Rs) of single hippocampal neuron was detected by perforated patch-clamp recordings. The results showed that, the slope of field excitatory postsynaptic potential (fEPSP) and carbachol-induced theta oscillation were significantly decreased in the hippocampal CA1 neurons of α7 KO mice, compared with those of wild type mice. Under the treatment of GABAA-R agonist muscimol, the I-V curves of both the hippocampal CA1 and CA3 neurons of α7 KO mice shifted towards depolarizing direction obviously, compared with those of wild type mice. These results suggest that the hippocampal CA3-CA1 synaptic transmission in α7 KO mice was significantly impaired and GABAA-R maturation was significantly delayed, indicating that the deletion of α7-nAChR gene could significantly change the electrophysiological function of the hippocampus. The results may provide a new understanding of the role of α7-nAChR in hippocampal function and associated diseases.

[ß2-nicotinic acetylcholine receptor promotes development of GABAA receptors in mouse hippocampal CA1 and CA3 pyramidal neurons].

OBJECTIVE: To explore the role of ß2-nicotinic acetylcholine receptor (ß2-nAChR) in the development of γ- aminobutyric acid A type receptors (GABAA-Rs) in hippocampal CA1 and CA3 pyramidal neurons of mice. METHODS: The hippocampal CA1 and CA3 pyramidal neurons were acutely isolated from ß2-nAChR gene knockout (ß2-KO group) mice. GABA currents in CA1 and CA3 pyramidal neurons were induced with the selective GABAA-R agonist muscimol and recorded using perforated patch-clamp recording technique. The GABA currents of CA1 and CA3 pyramidal neurons were tested for their equilibrium potentials (EMuss) and kinetic parameters and were compared with the measurements in wild-type mice (WT group). RESULTS: The mean EMus of CA1 neurons (n=7) of ß2-KO mice (n=4) was -31.7±3.5 mV, showing an obvious depolarizing shift compared with the WT mice (P < 0.05); the mean EMus of CA3 neurons (n=4) was -16.1±4.6 mV, also showing a depolarizing shift (P < 0.01). The difference in the EMuss between CA3 and CA1 neurons in ß2-KO mice, but not in WT mice, was significant (P < 0.05). The GABAA-R desensitization was significantly slowed down in both CA1 and CA3 neurons of ß2-KO mice, with decay time of 2.2±0.2 s and 3.2±0.1 s, respectively, significantly longer than those in WT mice (1.6±0.1 s and 2.3±0.1 s, respectively; P < 0.05). CONCLUSIONS: ß2-containing nAChRs may promote the functional maturation of GABAA-R in CA1 and CA3 pyramidal cells in mouse hippocampus.

Suppression of synaptic plasticity by fullerenol in rat hippocampus in vitro.

Fullerenol, a water-soluble fullerene derivative, has attracted much attention due to its bioactive properties, including the antioxidative properties and free radical scavenging ability. Due to its superior nature, fullerenol represents a promising diagnostic, therapeutic, and protective agent. Therefore, elucidation of the possible side effects of fullerenol is important in determining its potential role. In the present study, we investigated the acute effects of 5 µM fullerenol on synaptic plasticity in hippocampal brain slices of rats. Incubation with fullerenol for 20 minutes significantly decreased the peak of paired-pulse facilitation and long-term potentiation, indicating that fullerenol suppresses the short- and long-term synaptic plasticity of region I of hippocampus. We found that fullerenol depressed the activity and the expression of nitric oxide (NO) synthase in hippocampus. In view of the important role of NO in synaptic plasticity, the inhibition of fullerenol on NO synthase may contribute to the suppression of synaptic plasticity. These findings may facilitate the evaluation of the side effects of fullerenol.

The role of low levels of fullerene C60 nanocrystals on enhanced learning and memory of rats through persistent CaMKII activation.

Engineered nanomaterials are known to exhibit diverse and sometimes unexpected biological effects. Fullerene nanoparticles have been reported to specifically bind to and elicit persistent activation of hippocampal Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), a multimeric intracellular serine/threonine kinase central to Ca(2+) signal transduction and critical for synaptic plasticity, but the functional consequence of that modulation is unknown. Here we show that low doses of fullerene C60 nanocrystals (Nano C60), delivered through intrahippocampal infusion and without any obvious cytotoxicity in hippocampal neuronal cells, enhance the long-term potentiation (LTP) of rats. Intraperitoneal injection of 320 µg/kg of Nano C60, once daily for 10 days, also enhanced spatial memory of rats in addition to an increase of LTP. In parallel, both the IH and IP administration of Nano C60 increased the autonomous activity and the level of threonine 286 (T286) autophosphorylation of CaMKII, enhanced post-synaptic AMPA/NMDA ratio, and triggered time-dependent activation of ERK and CREB. Our results reveal a striking and highly unexpected ability of Nano C60 in positively modulating learning and memory, an effect that is most likely manifested through locking CaMKII in an active conformation, and may have significant implications for the potential therapeutic applications of fullerene C60, a classic engineered nanomaterial.

The role of elevated autophagy on the synaptic plasticity impairment caused by CdSe/ZnS quantum dots.

It is well known that autophagy, a cellular stress response to degrade damaged components, can be activated by many nanoparticles. We have demonstrated that CdSe/ZnS quantum dots (QDs), which are widely applied in vitro for diagnostics and cellular imaging, can impair synaptic transmission and synaptic plasticity in the dentate gyrus (DG) area, but the mechanism is still unclear. Here we show that elevated autophagy is at least partly responsible for this synaptic dysfunction induced by QDs in vivo. QDs elicited autophagy in the HeLa cells and cultured hippocampal neurons as well, accompanied with GFP-light chain protein 3 (LC3) puncta dots and autophagosome formation, extensive conversion of LC3-I to LC3-II and a significant decrease of p62. Furthermore, we found that autophagy inhibitors (wortmannin, 3-MA or chloroquine) suppressed QDs-induced autophagic flux, partly blocked LTP impairment, coincident with down-regulation of synapsin-I and synapse deficits by QDs in the hippocampal CA1 area. Our studies have important implications in providing a potential clinical remedy for brain damage caused by nanomaterials and in designing safer nanoparticles.

Concentration-dependent effects of fullerenol on cultured hippocampal neuron viability.

BACKGROUND: Recent studies have shown that the biological actions and toxicity of the water-soluble compound, polyhydroxyfullerene (fullerenol), are related to the concentrations present at a particular site of action. This study investigated the effects of different concentrations of fullerenol on cultured rat hippocampal neurons. METHODS AND RESULTS: Fullerenol at low concentrations significantly enhanced hippocampal neuron viability as tested by MTT assay and Hoechst 33342/propidium iodide double stain detection. At high concentrations, fullerenol induced apoptosis confirmed by Comet assay and assessment of caspase proteins. CONCLUSION: These findings suggest that fullerenol promotes cell death and protects against cell damage, depending on the concentration present. The concentration-dependent effects of fullerenol were mainly due to its influence on the reduction-oxidation pathway.

Effects of developmental exposure to TiO2 nanoparticles on synaptic plasticity in hippocampal dentate gyrus area: an in vivo study in anesthetized rats.

With the increasing applications of titanium dioxide nanoparticles (TiO(2) NPs) in industry and daily life, an increasing number of studies showed that TiO(2) NPs may have negative effects on the respiratory or metabolic circle systems of organisms, while very few studies focused on the brain central nervous system (CNS). Synaptic plasticity in hippocampus is believed to be associated with certain high functions of CNS, such as learning and memory. Thus, in this study, we investigated the effects of developmental exposure to TiO(2) NPs on synaptic plasticity in rats' hippocampal dentate gyrus (DG) area using in vivo electrophysiological recordings. The input/output (I/O) functions, paired-pulse reaction (PPR), field excitatory postsynaptic potential, and population spike amplitude were measured. The results showed that the I/O functions, PPR, and long-term potentiation were all attenuated in lactation TiO(2) NPs-exposed offspring rats compared with those in the control group. However, in the pregnancy TiO(2) NPs exposure group, only PPR was attenuated significantly. These findings suggest that developmental exposure to TiO(2) NPs could affect synaptic plasticity in offspring's hippocampal DG area in vivo, which indicates that developmental brains, especially in lactation, are susceptible to TiO(2) NPs exposure. This study reveals the potential toxicity of TiO(2) NPs in CNS. It may give some hints on the security of TiO(2) NPs production and application and shed light on its future toxicological studies.