Glutamate-Mediated Neural Alterations in Lead Exposure: Mechanisms, Pathways, and Phenotypes

Abstract

Lead (Pb) is a pervasive neurotoxicant with well-documented detrimental effects on the central nervous system, particularly in vulnerable populations such as children. Despite historical recognition of its toxicity, Pb exposure remains a significant public health concern due to its environmental persistence, historical industrial use, and ongoing applications in modern technologies. This review focuses on the mechanisms by which Pb disrupts glutamatergic signaling, a critical pathway for learning, memory, and synaptic plasticity. Pb’s interference with glutamate receptors (ionotropic NMDA and AMPA, as well as metabotropic receptors), transporters (EAATs, VGLUTs, and SNATs), and metabolic pathways (glutamate–glutamine cycle, TCA cycle, and glutathione synthesis) are detailed. By mimicking divalent cations like Ca2+ and Zn2+, Pb2+ disrupts calcium homeostasis, exacerbates excitotoxicity, and induces oxidative stress, ultimately impairing neuronal communication and synaptic function. These molecular disruptions manifest cognitive deficits, behavioral abnormalities, and increased susceptibility to neurodevelopmental and neurodegenerative disorders. Understanding Pb’s impact on glutamatergic neurotransmission offers critical insights into its neurotoxic profile and highlights the importance of addressing its effects on neural function.