Prenatal cyanuric acid exposure induced spatial learning impairments associated with alteration of acetylcholine-mediated neural information flow at the hippocampal CA3-CA1 synapses of male rats.

Cyanuric acid (CA) is reported to induce nephrotoxicity but its toxic effect is not fully known. Prenatal CA exposure causes neurodevelopmental deficits and abnormal behavior in spatial learning ability. Dysfunction of the acetyl-cholinergic system in neural information processing is correlated with spatial learning impairment and was found in the previous reports of CA structural analogue melamine. To further investigate the neurotoxic effects and the potential mechanism, the acetylcholine (ACh) level was detected in the rats which were exposed to CA during the whole of gestation. Local field potentials (LFPs) were recorded when rats infused with ACh or cholinergic receptor agonist into hippocampal CA3 or CA1 region were trained in the Y-maze task. We found the expression of ACh in the hippocampus was significantly reduced in dose-dependent manners. Intra-hippocampal infusion of ACh into the CA1 but not the CA3 region could effectively mitigate learning deficits induced by CA exposure. However, activation of cholinergic receptors did not rescue the learning impairments. In the LFP recording, we found that the hippocampal ACh infusions could enhance the values of phase synchronization between CA3 and CA1 regions in theta and alpha oscillations. Meanwhile, the reduction in the coupling directional index and the strength of CA3 driving CA1 in the CA-treated groups was also reversed by the ACh infusions. Our findings are consistent with the hypothesis and provide the first evidence that prenatal CA exposure induced spatial learning defect is attributed to the weakened ACh-mediated neuronal coupling and NIF in the CA3-CA1 pathway.

Maternal immune activation-induced proBDNF-mediated neural information processing dysfunction at hippocampal CA3-CA1 synapses associated with memory deficits in offspring.

Prenatal exposure to maternal infection increases the risk of offspring developing schizophrenia in adulthood. Current theories suggest that the consequences of MIA on mBDNF secretion may underlie the increased risk of cognitive disorder. There is little evidence for whether the expression of its precursor, proBDNF, is changed and how proBDNF-mediated signaling may involve in learning and memory. In this study, proBDNF levels were detected in the hippocampal CA1 and CA3 regions of male adult rats following MIA by prenatal polyI:C exposure. Behaviorally, learning and memory were assessed in contextual fear conditioning tasks. Local field potentials were recorded in the hippocampal CA3-CA1 pathway. The General Partial Directed Coherence approach was utilized to identify the directional alternation of neural information flow between CA3 and CA1 regions. EPSCs were recorded in CA1 pyramidal neurons to explore a possible mechanism involving the proBDNF-p75NTR signaling pathway. Results showed that the expression of proBDNF in the polyI:C-treated offspring was abnormally enhanced in both CA3 and CA1 regions. Meanwhile, the mBDNF expression was reduced in both hippocampal regions. Intra-hippocampal CA1 but not CA3 injection with anti-proBDNF antibody and p75NTR inhibitor TAT-Pep5 effectively mitigated the contextual memory deficits. Meanwhile, reductions in the phase synchronization between CA3 and CA1 and the coupling directional indexes from CA3 to CA1 were enhanced by the intra-CA1 infusions. Moreover, blocking proBDNF/p75NTR signaling could reverse the declined amplitude of EPSCs in CA1 pyramidal neurons, indicating the changes in postsynaptic information processing in the polyI:C-treated offspring. Therefore, the changes in hippocampal proBDNF activity in prenatal polyI:C exposure represent a potential mechanism involved in NIF disruption leading to contextual memory impairments.

Aluminum Oxide Nanoparticles Impair Working Memory and Neuronal Activity through the GSK3ß/BDNF Signaling Pathway of Prefrontal Cortex in Rats.

Studies demonstrated that alumina nanoparticles (alumina NPs) impair spatial cognition and hippocampus-dependent synaptic plasticity. Although alumina NPs accumulate in the prefrontal cortex (PFC), their effects on PFC-mediated neuronal and cognitive function have been not yet documented. Here, alumina NPs (10 or 20 µg/kg of body weight) were bilaterally injected into the medial PFC (mPFC) of adult rats, and the levels of glycogen synthase kinase 3ß (GSK3ß) and the brain-derived neurotrophic factor (BDNF) were detected. The PFC-dependent working memory task with one-minute or three-minute delay time was conducted. Meanwhile, the neuronal correlates of working memory performance were recorded. The specific expression of neuronal BDNF was assessed by colabeled BDNF expression with the neuronal nuclear antigen (NeuN). Whole-cell patch-clamp recordings were employed to detect neuronal excitability. Intra-mPFC alumina NP infusions significantly enhanced the expression of GSK3ß but reduced the phosphorylation of GSK3ß (pGSK3ß) and BDNF levels more severely at a dose of 20 µg/kg. Alumina NPs acted in a dose-dependent manner to impair working memory. The neuronal expression of BDNF in the 20 µg/kg group was markedly declined compared with the 10 µg/kg group. During the delay time, the neuronal frequency of pyramidal cells but not interneurons was significantly weakened. Furthermore, both the frequency and amplitude of the excitatory postsynaptic currents (EPSCs) were descended in the mPFC slices. Additionally, the infusion of GSK3ß inhibitor SB216763 or BDNF could effectively attenuate the impairments in neuronal correlate, neuronal activity, and working memory. From the perspective of the identified GSK3ß/BDNF pathway, these findings demonstrated for the first time that alumina NPs exposure can be a risk factor for prefrontal neuronal and cognitive functions.

Co-exposure of melamine and cyanuric acid as a risk factor for oxidative stress and energy metabolism: Adverse effects on hippocampal neuronal and synaptic function induced by excessive ROS production.

Melamine (MEL) and cyanuric acid (CA) alone have relatively low toxicity, but together they may cause serious damage to multiple organs, including the central nervous system, however, the underlying mechanism is unknown. This study aimed to determine and compare the neurotoxic effects of MEL (20 µg/mL), CA (20 µg/mL) and their combination (10 µg/mL MEL and 10 µg/mL CA) on cultured hippocampal neurons. The cell viability, apoptosis, anti-oxidative and energy metabolic indices were detected following 24 h of incubations. The miniature excitatory postsynaptic currents (mEPSCs), miniature inhibitory postsynaptic currents (mIPSCs) and synaptic plasticity in the hippocampal CA1 neurons were recorded. Moreover, ROS scavenger NAC was co-infused to investigate the potential mechanism. We found the complex of MEL and CA but not their alone caused severe cell death and disturbed energy production through activation caspase-3-mediated apoptosis. Meanwhile, the combination significantly reduced the amplitude, decay time and frequency of mEPSCs but not mIPSCs, indicating the pre- and post-synaptic inhibitory actions on neuronal activity. Paired-pulsed ratio (PPR) and long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses were critically depressed. However, the co-application of NAC could effectively mitigate the cellular apoptosis, energy metabolism dysfunction and the impairments in neuronal and synaptic function. Our findings provide the first evidence that the combination of MEL and CA can exert more prominently neurotoxic effects than their alone and certify that one of the potential mechanisms for neuronal and synaptic dysfunction is the ROS-mediated signaling pathway.

Prenatal cyanuric acid exposure disrupts cognitive flexibility and mGluR1-mediated hippocampal long-term depression in male rats.

Cyanuric acid is one of the most widely used classes of industrial chemicals and is now well known as food adulterant and contaminant in pet food and infant formula. Previously, it was reported that animals prenatally exposed to cyanuric acid showed neurotoxic effects that impaired memory consolidating and suppressed long-term potentiation (LTP) in the hippocampus. However, it is not clear if prenatal exposure to cyanuric acid induces deficits in reversal learning and long-term depression (LTD), which is required for the developmental reorganization of synaptic circuits and updating learned behaviors. Here, pregnant rats were i.p. injected with cyanuric acid (20 mg/kg) during the whole of gestation, and male offspring were selected to examine the levels of hippocampal mGluR1 and mGluR2/3 in young adulthood. The LTD at the Schaffer collateral-CA1 pathway was induced by low-frequency stimulation (LFS) and recorded. Reversal learning and hippocampus-dependent learning strategy were tested in Morris-water maze (MWM) and T-maze tasks, respectively. To further confirm the potential mechanism, selective agonists of mGluR1 and mGluR2/3 and antagonists of mGluR were intra-hippocampal infused before behavioral and neuronal recording. We found the levels of alkaline phosphatase were markedly increased in the maternal placenta and fetal brain following prenatal exposure. The expression of mGluR1 but not mGluR2/3 was significantly decreased and mGluR1-mediated LTD was selectively weakened. Prenatal cyanuric acid impaired reversal learning ability, without changing place learning strategy. The mGluR1 agonist could effectively enhance LFS-induced LTD and mitigate reversal learning deficits. Meanwhile, the reductions in the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-mediated spontaneous excitatory postsynaptic currents (sEPSCs) amplitude and frequency of cyanuric acid offspring were simultaneously alleviated by mGluR1 agonist infusions. Therefore, the results indicate the cognitive and synaptic impairments induced by prenatal cyanuric acid exposure are attributed to the disruption of the hippocampal mGluR1 signaling. Our findings provided the first evidence for the deteriorated effects of cyanuric acid on synaptic depression and advanced cognitive performance.

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

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 p75NTR 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-p75NTR 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 p75NTR, 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.

Prelimbic proBDNF Facilitates Retrieval-Dependent Fear Memory Destabilization by Regulation of Synaptic and Neural Functions in Juvenile Rats.

Fear regulation changes as a function of the early life is a key developmental period for the continued maturation of fear neural circuitry. The mechanisms of fear retrieval-induced reconsolidation have been investigated but remain poorly understood. The involvement of prelimbic proBDNF in fear memory extinction and its mediated signaling have been reported previously. Specifically, blocking the proBDNF/p75NTR pathway during the postnatal stage disrupts synaptic development and neuronal activity in adulthood. Given the inherent high expression of proBDNF during the juvenile period, we tested whether the prelimbic proBDNF regulated synaptic and neuronal functions allowing to influencing retrieval-dependent memory processing. By examining the freezing behavior of auditory fear-conditioned rats, we found the high level of the prelimbic proBDNF in juvenile rats enhanced the destabilization of the retrieval-dependent weak but not strong fear memory through activating p75NTR-GluN2B signaling. This modification of fear memory traces was attributed to the increment in the proportion of thin-type spine and promotion in synaptic function, as evidenced by the facilitation of NMDA-mediated EPSCs and GluN2B-dependent synaptic depression at the prelimbic projection. Furthermore, the strong prelimbic theta- and gamma-oscillation coupling predicted the suppressive effect of juvenile proBDNF on the recall of postretrieval memory. Our results critically emphasize the importance of developmental proBDNF for modification of retrieval-dependent memory and provide a potential critical targeting to inhibit threaten memories associated with neurodevelopment disorders.

Prenatal cyanuric acid exposure depresses hippocampal synaptic plasticity and induces spatial learning and memory deficits.

The infant and fetus may be exposed to cyanuric acid (CA) via several different routes into the diet or milk product as well as deliberate contamination. Previous findings indicated chronic CA treatment caused neurotransmission and synaptic impairment in the early developing hippocampus. This study was designed to characterize the effects of different doses (10 mg/kg, 20 mg/kg and 40 mg/kg) of CA exposure on the developing fetus. Pregnant rats were intraperitoneally exposed to CA during the entire period of gestation and male offspring were selected for water maze task, neural recording and N-methyl-d-aspartate (NMDA) receptor detection around the eighth postnatal week. We found that CA exposure impaired the learning and memory function in a dose-dependent manner. The paired-pulse ratio (PPR) and GluN2A-dependent long-term potentiation (LTP) at the Schaffer collateral-CA1 pathway were affected in CA-exposed rats. Remarkably, hippocampal levels of NMDA-GluN2A, but not NMDA-GluN2B, were significantly decreased. Meanwhile, the spine density of hippocampal CA1 neurons was not altered by the CA exposure. Our findings are consistent with the hypothesis that CA treatment during the prenatal period produces deficits in spatial cognition by disrupting hippocampal synaptic function.