Impairments of Spatial Memory and N-methyl-d-aspartate Receptors and Their Postsynaptic Signaling Molecules in the Hippocampus of Developing Rats Induced by As, Pb, and Mn Mixture Exposure

• Published in: Brain sciences Vol. 13; no. 12; p. 1715
• Main Authors: Chandravanshi, Lalit P, Agrawal, Prashant, Darwish, Hany W, Trigun, Surendra Kumar
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01-12-2023
• Subjects: Animal cognition; Aspartate; Birth defects; Brain; Brain research; Ca2+/calmodulin-dependent protein kinase II; Cognition disorders; Cognitive ability; Cyclic AMP response element-binding protein; developmental neurotoxicity; Drinking water; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Hippocampal plasticity; Hippocampus; Kinases; Lead; Learning; Manganese; MAP kinase; Memory; Metals; Methyl aspartate; N-Methyl-D-aspartic acid receptors; Neurotoxicity; NMDA receptors; Postsynaptic density; Postsynaptic density proteins; Proteins; PSD-95; Public health; Ras protein; Spatial memory; Synaptic density; Synaptic plasticity; India; United States > US; NMDA receptors; PSD-95; developmental neurotoxicity; spatial memory
• ISSN: 2076-3425; 2076-3425
• DOI: 10.3390/brainsci13121715

Exposure to metal mixtures is recognized as a real-life scenario, needing novel studies that can assess their complex effects on brain development. There is still a significant public health concern associated with chronic low levels of metal exposure. In contrast to other metals, these three metals (As, Pb, and Mn) are commonly found in various environmental and industrial contexts. In addition to additive or synergistic interactions, concurrent exposure to this metal mixture may also have neurotoxic effects that differ from those caused by exposure to single components. The NMDA receptor and several important signaling proteins are involved in learning, memory, and synaptic plasticity in the hippocampus, including CaMKII, postsynaptic density protein-95 (PSD-95), synaptic Ras GTPase activating protein (SynGAP), a negative regulator of Ras-MAPK activity, and CREB. We hypothesized that alterations in the above molecular players may contribute to metal mixture developmental neurotoxicity. Thus, the aim of this study was to investigate the effect of these metals and their mixture at low doses (As 4 mg, Pb 4 mg, and Mn 10 mg/kg bw/p.o) on NMDA receptors and their postsynaptic signaling proteins during developing periods (GD6 to PD59) of the rat brain. Rats exposed to As, Pb, and Mn individually or at the same doses in a triple-metal mixture (MM) showed impairments in learning and memory functions in comparison to the control group rats. Declined protein expressions of NR2A, PSD-95, p- CaMKII, and pCREB were observed in the metal mix-exposed rats, while the expression of SynGAP was found to be enhanced in the hippocampus as compared to the controls on PD60. Thereby, our data suggest that alterations in the NMDA receptor complex and postsynaptic signaling proteins could explain the cognitive dysfunctions caused by metal-mixture-induced developmental neurotoxicity in rats. These outcomes indicate that incessant metal mixture exposure may have detrimental consequences on brain development.