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 glutam ate and GABA receptors were examined by in situ hybridization histoche mistry after treatment of rat hippocampal slice cultures with convulsa nts. Application of 500 mu M picrotoxin for two days led to decreases in the messenger RNA levels for the N-methyl-D-aspartate receptor subu nits, NR2A and NR2B, and for the non-N-methyl-D-aspartate receptor sub units, glutamate receptors 1 and glutamate receptors 2, to about 50% o f 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 kai nate receptor subunits 1 and 2; and the GABA(A) receptor subunits, alp ha(2), beta(2), gamma(2) were unchanged. Decreased levels of expressio n were no longer seen five days after removal of convulsant. The down- regulation could be prevented by co-application of both the non-N-meth yl-D-aspartate and N-methyl-D-aspartate receptor antagonists, 6-cyano- 7-nitroquinoxaline-2,3-dione (CNQX) and dizocilpine maleate, but not b y applying each alone. Application of CNQX or dizocilpine maleate in t he absence of picrotoxin also resulted in changes in glutamate recepto r expression. We suggest that the convulsant-induced reduction in glut amate receptor expression leads to a decreased excitability in these c ultures, and that this down-regulation represents a compensatory react ion of hippocampal pyramidal cells to enhanced excitatory input.