Developmental lead (Pb) exposure reduces the ability of the NMDA antagonist MK-801 to suppress long-term potentiation (LTP) in the rat dentate gyrus, in vivo.
Chronic developmental lead (Pb) exposure increases the threshold and enhances decay of long-term potentiation (LTP) in the dentate gyrus of the hippocampal formation. MK-801 and other antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype impair induction of LTP. In addition, Pb exposure reduces presynaptic glutamate release and is associated with alterations in NMDA receptor expression. This study examined LTP in Pb-exposed animals challenged with a low dose of MK-801 to assess the sensitivity of this receptor to inhibition. Pregnant rats received 0.2% Pb acetate in the drinking water beginning on gestational day 16, and this regimen was continued through lactation. Adult male offspring maintained on this solution from weaning were prepared with indwelling electrodes in the perforant path and dentate gyrus. Several weeks later, input/output (I/O) functions were collected in awake animals before and after saline or MK-801 administration (0.05 mg/kg, s.c.). LTP was induced using suprathreshold train stimuli 60 min post-drug. Post-train I/O functions were reassessed 1 and 24 h after train delivery. Upon full decay of any induced LTP, drug conditions were reversed such that each animal was tested under saline and MK-801. I/O functions measured 1 and 24 h after train induction as well as immediate post-train responses revealed significant LTP of comparable magnitude that was induced in both control and Pb-exposed animals tested under saline conditions. In contrast, MK-801 reduced LTP in control but not in Pb-exposed animals. The broadening of the excitatory postsynaptic potential evident in responses evoked by train stimuli is NMDA-dependent. Pb exposure attenuated the MK-801-induced reduction in area of this NMDA component by approximately 50%. These findings are consistent with other neurochemical and behavioural observations and suggest that up-regulation of postsynaptic NMDA receptors produces subsensitivity to the inhibitory effects of MK-801 on hippocampal LTP following chronic developmental Pb exposure.
Gilbert
M E
ME
Neurotoxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711, USA. gilbert.mary@epa.gov
Lasley
S M
SM
D000818:Animals; D018891:Dentate Gyrus / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics / Q000494:pharmacology*; D004558:Electric Stimulation; D004567:Electrodes, Implanted; D004594:Electrophysiology; D005071:Evoked Potentials / Q000187:drug effects; D018690:Excitatory Amino Acid Agonists / Q000493:pharmacokinetics / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005260:Female; D020263:Lead Poisoning, Nervous System / Q000503:physiopathology*; D017774:Long-Term Potentiation / Q000187:drug effects*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors*; D051381:Rats; D020318:Rats, Long-Evans; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate