CHANGES IN GENE-EXPRESSION OF AMPA-SELECTIVE GLUTAMATE-RECEPTOR SUBUNITS INDUCED BY STATUS EPILEPTICUS IN RAT-BRAIN

In the present investigation we address the question of whether one of the responses to increased neuronal activity is a modification of the expression of the different subunits of alpha-amino-3-hydroxy-5-methy l-4-isoxazole propionate (AMPA)-selective glutamate receptors (GluR-1, GluR-2, GluR-3). Thus, we used two different models of generalized st atus epilepticus, as widespread elevated neuronal activity, to study i n vivo responses of the AMPA receptor mRNA expression in rat forebrain . By Northern blot analysis and in situ hybridization, we show that on e of the delayed responses to LiCl/pilocarpine-induced status epilepti cus is a dramatic change in the mRNA level of some subunits of AMPA-se lective glutamate receptors. These effects, which appear between 6 and 12 h after the drug treatment, are subunit and brain region specific. The most striking example of differential expression of the three exa mined GluR mRNAs can be observed in the dentate gyrus of the hippocamp us. In this specific brain subregion an increase of GluR-3 mRNA level is induced 12 h after LiCl/pilocarpine treatment, while a clear decrea se in GluR-1 mRNA level and no significant change in GluR-2 mRNA level can be observed in the same area under these experimental conditions. Both the GluR-1 decrease and the GluR-3 increase are transient effect s and a return to basal level can be observed after 48-72 h. In the CA 1 layer of the hippocampus, a parallel decrease of both GluR-1 and Glu R-3 expression is found 12-24 h after drug treatment, followed by a re covery of the expression to control values at 48 h. In kainate-induced epilepsy we could reproduce the late increase (12-24 h) in GluR-3 mRN A in the dentate gyrus;however, under this experimental condition, no clear decrease of GluR-1 expression can be observed in this area. A ge neral decrease in mRNA level for the AMPA receptor subunits (GluR-1-3) in the hippocampal layers, in particular in CA3 and CA4 subfields, wa s also observed. In conclusion the results reported in the present pap er reveal a specific regulation of GluR gene expression in the granule cells of the hippocampal dentate gyrus and stimulate further investig ation on the functional role of the GluR-3 subunit in the receptor-cha nnel complex.