Altered sensitivity to NMDA following developmental lead exposure in rats
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Published on: December 14, 2014
T L Petit1, J C LeBoutillier, W J Brooks
1Department of Psychology, University of Toronto, Scarborough, Ontario, Canada.
Insights
Early lead (Pb) exposure alters N-methyl-D-aspartate (NMDA) sensitivity in developing rats, increasing seizure susceptibility and neurotoxicity. Higher lead levels led to greater NMDA-induced effects and mortality.
Area of Science:
- Neuroscience
- Developmental Toxicology
- Neuropharmacology
Background:
- Early lead (Pb) exposure is a known neurotoxicant affecting hippocampal development.
- This can lead to impaired learning, memory, and altered seizure susceptibility.
- N-methyl-D-aspartate (NMDA) receptors in the hippocampus are crucial for learning, memory, and seizure activity.
Purpose of the Study:
- To investigate the impact of early lead exposure on NMDA-induced neurotoxicity and seizure susceptibility in rat pups.
- To determine if lead exposure alters the dose-response relationship of NMDA in developing animals.
Main Methods:
- Rat pups were exposed to varying dietary levels of lead carbonate (PbCO3) or a control diet from postnatal day 1 to 25.
- NMDA was administered via injection to rat pups at postnatal days 15 and 25.
- Behavioral responses and mortality following NMDA administration were recorded.
Main Results:
- Control rats exhibited typical NMDA responses at specific doses.
- Lead-exposed rats showed increased sensitivity to NMDA, with lower doses causing behavioral signs and death.
- The severity of NMDA-induced effects and mortality correlated with the level of lead exposure.
- Low lead exposure resulted in a variable and reduced response to NMDA.
Conclusions:
- Early lead exposure significantly alters NMDA receptor function and sensitivity in the developing hippocampus.
- Lead-induced neurotoxicity enhances susceptibility to NMDA-mediated excitotoxicity and seizures.
- These findings highlight critical developmental windows for lead's neurotoxic effects on neurotransmission.
Abstract:
Early Pb exposure is known to disrupt the development of the hippocampus and result in deficits in learning and memory capacities and altered seizure susceptibility. The excitatory amino acid, NMDA, is found in high concentrations in the hippocampus and has been implicated in learning and memory functions and seizure activity. Rat pups nursed mothers exposed to high (4%), moderate (0.4%), or low (0.05%) levels of PbCO3 in their diet, or a Na2CO3 control diet from postnatal day 1 (P1) to P25. Rat pups were injected with varying doses of NMDA on P15 or P25. Control animals showed a characteristic slowly developing response to NMDA, usually including tail twitches and wet dog shakes at approximately 10 and 40 mg/kg at P15 and P25, respectively, with status epilepticus and death occurring at 40 and 80 mg/kg. Lead-exposed animals displayed an altered sensitivity to NMDA, with high and medium Pb animals showing the onset of behavioral signs and death at lower NMDA doses, the degree of which being dependent on the level of Pb exposure. Low Pb-exposed animals showed a more variable and attenuated response to NMDA. The data are discussed in terms of the possible mechanisms of Pb neurotoxicity.
