Scientists at the Johns Hopkins School of Public Health have identified a molecular mechanism whereby lead poisoning cripples learning and memory. Many studies have shown that lead poisoning impairs learning and memory, but this is the first to pinpoint a particular part of the nervous system that is significantly altered in the brains of lead-poisoned animals. The researchers also discovered that blood-lead levels did not accurately reflect lead concentrations in the brain. The study appears in the August 2000 issue of Neuroscience.
Senior author Tomás R. Guilarte, PhD, professor, Environmental Health Sciences, Johns Hopkins School of Public Health, said, “It has been known for some time that lead is a potent inhibitor of the NMDA receptor, a protein known to play an important role in brain development and cognition. In this study we demonstrate that lead exposure decreased the amount of NMDA receptor gene and protein in a part of the brain called the hippocampus. This change is associated with impairments of nerve communication in the brain and of learning.”
The experiments marked the first time researchers have looked into multiple facets of lead poisoning in a single study: First, the toxic metal’s effects on learning behavior; second, how it affects the communication between neurons; and third, which genes and proteins crucial to nervous system development are adversely affected by lead. Since all pups born into the same litter have virtually identical genetic make-ups, the researchers were careful to study these three parameters in rats from multiple litters, to make sure that any detected abnormalities were due to lead and not to some genetic anomaly found within one family.
Rats were given either 0, 750, or 1500 parts per million (ppm) of lead acetate through their diet, which made their blood-lead levels comparable to those detected in lead-poisoned children in the United States. The study was three-pronged, with lead-poisoned and control animals randomly assigned to one of three experiments.
To study the effect of lead on learning and memory, the first group of animals were taught to find the location of a hidden platform submerged in a pool of opaque water. In this water maze study, the lead-poisoned animals were significantly slower to find the platform than controls, indicating that their learning of the new skill was poor.
Litter mates to these animals were used in studies measuring how responsive particular groups of cells in the brain are to stimuli. Since the synapses between neurons are thought to be strengthened during the process of learning, the researchers measured how well a group of neurons in the hippocampus could communicate to form a neural pathway. This set of experiments, carried out by Nancy L. Desmond, PhD, assistant professor, Neurosurgery, University of Virginia, Charlottesville, showed that the synapses of the control rats responded readily to the conditioning, smoothly transmitting the stimulus again and again over time. In contrast, the neurons of rats exposed to lead were not able to establish strong links with each other during the conditioning period.
The third group of rats underwent molecular studies to determine exactly what part of the neuron was being changed by lead. The researchers focused on a tiny portion of the neuron called the NMDA receptor, long known to play an important role in learning and memory. This experiment showed that long-term exposure to lead in adult rats alters the expression of particular genes and proteins that make up the NMDA receptor.
“We believe that lead, by decreasing these NMDA receptors, is interfering with calcium’s entry into the neuron,” says first author Michelle K. Nihei, PhD, research associate, Environmental Health Sciences, Johns Hopkins School of Public Health. “This is noteworthy since calcium is responsible for a huge cascade of cellular signals that ultimately propagate information and continue the nerve impulse on to the next synapse and neuron.”
This was the first study to show not only that the NMDA receptor in animals was changed by lead, but also that the problems in learning and within the neuronal connections themselves were due to lead poisoning. The authors go on to say that studies like this one significantly advance the understanding of lead neurotoxicity and, perhaps more importantly, may guide researchers in the right direction to find interventions to ameliorate the consequences of childhood lead poisoning.