Chronic melamine cyanurate exposure impairs spatial learning and memory by altering autophagy-mediated synaptic plasticity and oxidative stress in the hippocampus of adolescent rats.

Either melamine or cyanuric acid alone has low toxicity, but melamine-cyanuric acid crystals co-crystals melamine cyanurate (MC) is reported to cause renal toxicity and has latent effects on central nervous system. This study investigated the neurotoxic effects and mechanism of MC on hippocampus-dependent cognitive and synaptic function using a rat model administered MC during early postnatal stage. We tested the spatial learning and memory ability in Morris water maze (MWM) test and recorded hippocampal long-term potential (LTP) at CA1 synapses. Furthermore, we examined whether autophagy was involved in MC-induced cognitive, synaptic and oxidative damages. We found that MC given at a dose of 30 mg/kg/day for 28 consecutive days significantly impaired spatial performance without affecting locomotion or short-term memory ability. Hippocampal LTP at Shaffer-collateral-CA1 synapses was dramatically depressed while the presynaptic form of synaptic plasticity paired-pulse facilitation (PPF) and basal neurotransmission were not changed. Meanwhile, MC declined the expression postsynaptic GluN2A but not GluN2B subunits of N-methyl-D-aspartate (NMDA) receptors and the postsynaptic density protein 95 (PSD-95) level was also reduced. Autophagy in the hippocampus was down-regulated by MC, as indicated by reduction in the levels of Beclin-1and LC3-II, and the ratio of LC3II/LC3I. However, up-regulation of autophagy by rapamycin could effectively alleviate cognitive deficits and synaptic dysfunction. Meanwhile, retrieval of autophagic activity restored oxidation-antioxidation homeostasis, by elevating MC-declined superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) and suppressing MC-enhanced superoxide anion radical, hydroxyl free radical and malondialdehyde (MDA). Additionally, MC elevated the caspase-3 activity and caused the apoptotic cell death, which was mitigated by rapamycin treatment. However, inhibition of autophagy further deteriorated MC-induced these impairments. Therefore, we demonstrate that MC induces cognitive impairments at least due to oxidative damage and synaptic dysfunction through postsynaptic actions, which can be further attributed to the down-regulation autophagy.