Aluminium oxide nanoparticles compromise spatial memory performance and proBDNF-mediated neuronal function in the hippocampus of rats

Abstract

Background: Alumina nanoparticles (aluminaNPs), which are widely used in a range of daily and medical fields, have been shown to penetrate blood-brain barrier, and distribute and accumulate in different brain areas. Although oral treatment of aluminaNPs induces hippocampus-dependent learning and memory impairments, characteristic effects and exact mechanisms have not been fully elucidated. Here, male adult rats received a single bilateral infusion of aluminaNPs (10 or 20 µg/kg of body weight) into the hippocampal region, and their behavioral performance and neural function were assessed.

Results: The results indicated that the intra-hippocampus infusions at both doses of aluminaNPs did not cause spatial learning inability but memory deficit in the water maze task. This impairment was attributed to the effects of aluminaNP on memory consolidation phase through activation of proBDNF/RhoA pathway. Inhibition of the increased proBDNF by hippocampal infusions of p75^NTR antagonist could effectively rescue the memory impairment. Incubation of aluminaNPs exaggerated GluN2B-dependent LTD induction with no effects on LTD expression in hippocampal slices. AluminaNP could also depress the amplitude of NMDA-GluN2B EPSCs. Meanwhile, increased reactive oxygen specie production was reduced by blocking proBDNF-p75^NTR pathway in the hippocampal homogenates. Furthermore, the neuronal correlate of memory behavior was drastically weakened in the aluminaNP-infused groups. The dysfunction of synaptic and neuronal could be obviously mitigated by blocking proBDNF receptor p75^NTR, implying the involvement of proBDNF signaling in aluminaNP-impaired memory process.

Conclusions: Taken together, our findings provide the first evidence that the accumulation of aluminaNPs in the hippocampus exaggeratedly activates proBDNF signaling, which leads to neural and memory impairments.

Keywords: Aluminum oxide nanoparticle; Hippocampal CA1 neuron; Memory consolidation; Neuronal activity; Synaptic plasticity.

Fig. 1

The performance in behavioral tests. A Mean escape latency calculated for each trial during the acquisition phase of the MWM task. B Effects of aluminaNP on STM, LTM and the memory retrieval during the probe trials. C Location of the nanoparticles in the hippocampal CA1 region. The yellow arrows indicated the location of the nanoparticles and the white scale bar presented at the bottom of the photomicrograph indicated 50 μm. D Total travel distance and E percentage of time spent in the center of the apparatus during the open field test. F Press time every min during the lever press test. Data are presented as mean ± SEM. *, P < 0.05, versus control group. The number of rats in each group was indicated in each column or legend

Fig. 2

Effects of aluminaNPs on mBDNF-CREB and proBDNF-RhoA signaling pathway. The levels of A mBDNF, B CREB, C proBDNF and D RhoA in the hippocampus. *, P < 0.05, versus control group. E Blocking proBDNF receptor p75^NTR activation can mitigate memory deficits. Data are presented as mean ± SEM. *, P < 0.05, versus other groups. The number of rats in each group was indicated in each legend

Fig. 3

Effects of aluminaNP on neuronal function in the hippocampal slices. A Input–output synaptic function. B Characteristic time courses of fEPSP slope. The bidirectional arrow indicated the application of LFS. C Time coursing changes in fEPSPs slope. The magnitude of LTD was determined as responses between 41 and 60 min after LFS. D A typical consecutive sample trace of NMDA-GluN2B EPSC from each group (left) and the frequency of NMDA-GluN2B EPSCs (right). E The amplitude of NMDA-GluN2B EPSCs. The levels of F superoxide anion radical and G hydroxyl free radical in the homogenates of hippocampal slices. Data are presented as mean ± SEM. *, P < 0.05, versus other groups. The number of rats in each group was indicated in each legend

Fig. 4

AluminaNP weakens neuronal correlate of memory behavior. A Distribution of mean firing rate and half-valley to half-peak ratio of each unit from the recording. B Firing rate of fast-spiking interneurons (IN) during the probe test. C Firing rate of pyramidal neurons (PN) during the probe test. Data are presented as mean ± SEM. *, P < 0.05, versus other groups. The number of rats in each group was indicated in each legend