Selective Alterations in Binding Kinetic Parameters and Allosteric Regulation of N-Methyl-D-Aspartate Receptors after Prolonged Seizures in the Developing Rat Brain

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Abstract

ABSTRACT

Among glutamate receptor subtypes, the N-methyl-D-aspartate(NMDA) receptor plays a key role in brain development and cognitive processes, and mediates excitotoxic injury. To test the hypothesis that prolonged seizures may affect NMDA receptor characteristics in the developing brain, a 30-min episode of generalized seizures was induced in rats at 5, 10, 15 and 25 d of age by i.p. administrations of bicuculline. NMDA receptors were analyzed using specific binding of [3H]-labeled(+)-5-methyl-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptene-5,10-imine maleate (MK-801) in brain membrane preparations, and allosteric regulation was studied by addition of glutamate (10 μM) and glycine (10 μM). In control pups, total number of binding sites increased between 5 and 25 d,Bmax values varying from 1032 ± 93 to 2311 ± 449 fmol/mg protein, whereas receptor affinity decreased with age, the affinity constant (Kd) changing from 20.9 ± 2.0 to 29.1 ± 2.0 nM. Activation of NMDA receptors by glutamate and glycine led to age-dependent decreases in Kd values, from 30% at 5 d to 72% at 25 d. Seizures altered receptor density only at 5 d (by 40%). Receptor affinity was increased after seizures at 5, 15 and 25 d (from 12 to 60%). The capacity of receptor activation by glutamate and glycine was significantly reduced by seizures at 5 d. There was no change either in density nor affinity of receptors at 10 d. Therefore, as previously shown for central adenosine and benzodiazepine receptors, sustained seizures are able to alter the characteristics of NMDA receptors in a specific way depending on the maturational stage, suggesting developmental changes in the mechanisms of brain response to seizures.

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