Elsevier

Neuroscience

Volume 99, Issue 2, 11 September 2000, Pages 233-242
Neuroscience

N-methyl-d-aspartate receptor subunit changes are associated with lead-induced deficits of long-term potentiation and spatial learning

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Abstract

The present study demonstrates that impairments of spatial learning and hippocampal long-term potentiation in rats chronically exposed to lead are associated with changes in gene and protein expression of N-methyl-d-aspartate receptor subunits. Rats exposed to 750 and 1500 ppm lead acetate were found to exhibit deficits in acquisition of a water maze spatial learning task. Furthermore, lead-exposed rats show dose-dependent reductions in the maintenance of in vivo hippocampal long-term potentiation induced in entorhinal cortex–dentate gyrus synapses. We found an unexpected, but significant (P<0.05), correlation between spatial learning and long-term potentiation when control and lead-exposed rats were analysed as a single, combined population. Dentate gyrus NR1 subunit messenger RNA was reduced 18% and 28% by exposure to 750 and 1500 ppm lead acetate, respectively. NR2A subunit messenger RNA was reduced 18% but only in the dentate gyrus of rats exposed to 1500 ppm lead acetate. No significant changes in dentate NR2B messenger RNA expression were measured in either of the lead-exposed groups. NR1 subunit protein was reduced 24% and 58% in hippocampal homogenates from rats exposed to 750 and 1500 ppm lead acetate. In contrast, no changes in NR2A or NR2B subunit protein were observed in the same hippocampal homogenates.

These data show that reductions of specific N-methyl-d-aspartate receptor subunits are associated with deficits of both hippocampal long-term potentiation and spatial learning, induced in rats by chronic exposure to environmentally relevant levels of lead. These findings strongly suggest that the effects of lead on N-methyl-d-aspartate receptors may be the mechanistic basis for lead-induced deficits in cognitive function.

Keywords

NMDA receptor
LTP
Pb2+
spatial learning
subunits

Abbreviations

ANOVA, analysis of variance
CA, cornu ammonis
EDTA, ethylenediaminetetra-acetate
LTP, long-term potentiation
NMDA, N-methyl-d-aspartate
NMDAR, N-methyl-d-aspartate receptor
P, postnatal day
PbAc, lead acetate
pEPSP, population excitatory postsynaptic potential
SSC, standard saline citrate

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