ALTERATIONS IN GLUTAMATE BUT NOT GABA(A) RECEPTOR SUBUNIT EXPRESSION AS A CONSEQUENCE OF EPILEPTIFORM ACTIVITY IN-VITRO

The consequences of epileptiform discharge on the expression of glutamate and GABA receptors were examined by in situ hybridization histochemistry after treatment of rat hippocampal slice cultures with convulsants. Application of 500 mu M picrotoxin for two days led to decreases in the messenger RNA levels for the N-methyl-D-aspartate receptor subunits, NR2A and NR2B, and for the non-N-methyl-D-aspartate receptor subunits, glutamate receptors 1 and glutamate receptors 2, to about 50% of the levels seen in control cultures. Messenger RNA levels for the N-methyl-D-aspartate receptor subunit, NR1; the non-N-methyl-D-aspartate receptor subunits, glutamate receptors 3 and 4; the high-affinity kainate receptor subunits 1 and 2; and the GABA(A) receptor subunits, alpha(2), beta(2), gamma(2) were unchanged. Decreased levels of expression were no longer seen five days after removal of convulsant. The down-regulation could be prevented by co-application of both the non-N-methyl-D-aspartate and N-methyl-D-aspartate receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and dizocilpine maleate, but not by applying each alone. Application of CNQX or dizocilpine maleate in the absence of picrotoxin also resulted in changes in glutamate receptor expression. We suggest that the convulsant-induced reduction in glutamate receptor expression leads to a decreased excitability in these cultures, and that this down-regulation represents a compensatory reaction of hippocampal pyramidal cells to enhanced excitatory input.