Neural overexcitation and implication of NMDA and AMPA receptors in a mouse model of temporal lobe epilepsy implying zinc chelation.
OBJECTIVE
Zinc chelation with diethyldithiocarbamate (DEDTC) during nondamaging kainic acid administration enhances excitotoxicity to the level of cell damage. The objective of this work was to study the developing of the lesion in this model of temporal lobe epilepsy and the implications of the different types of glutamate receptors.


METHODS
The antagonist of the N-methyl-D-aspartate (NMDA) receptor MK-801, and the antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor GYKI52466, were used concomitantly with intraperitoneal administration of kainic acid (15 mg/kg) followed by DEDTC (150 mg/kg) in mouse. The animals were killed at different times from 4 h to 7 days. Fos proteins were used as markers of cell overexcitation; heat-shock protein 72 (HSP72) as marker of cell stress.


RESULTS
Neither kainic acid nor DEDTC alone, at the doses used, led to cell loss, HSP72 expression, or permanent Fos protein induction. When combined, the hilus and cornu ammonis were damaged; principal cells in these areas coexpressed c-Fos and HSP72, with the exception of CA2; interneurons did not express HSP72 in any area. MK-801 completely abolished damage and HSP72 expression from the hippocampus. GYKI52466 blocked CA1 damage and HSP72 expression in the CA1 but not in the CA3.


CONCLUSIONS
Synaptic zinc increases the tolerance of hippocampus to overexcitation. All the areas that are fated to die are determined simultaneously; the damage in the CA1 is not an extension of the damage in the CA3. Damage of the CA3 is dependent on kainate and NMDA receptors, whereas the damage of the CA1 depends on AMPA and NMDA receptors.
Domínguez
María-Isabel
MI
Universidad de Valencia, Facultad de Ciencias Biológicas, Departamento de Biología Celular, Unidad de Neurobiología, Burjasot, Spain.
Blasco-Ibáñez
José-Miguel
JM
Crespo
Carlos
C
Nacher
Juan
J
Marqués-Marí
Ana-Isabel
AI
Martínez-Guijarro
Francisco-José
FJ