NMDA RECEPTOR BLOCKADE PREVENTS KAINATE INDUCTION OF PROTEIN F1 GAP-43 MESSENGER-RNA IN HIPPOCAMPAL GRANULE CELLS AND SUBSEQUENT MOSSY FIBER SPROUTING IN THE RAT/

Granule cells in the adult rat hippocampus do nor constitutively expre ss the growth-related axonal protein F1 (a.k.a. B-50, GAP-43, neuromod ulin, pp46), yet kainic acid (KA) can induce extensive growth of granu le cell axons, the messy fibers, into the supragranular layer. Does th is KA-induced growth occur in the absence of protein F1/GAP-43? Using quantitative in situ hybridization, we found that 16-24 h after KA (10 mg/kg, s.c.) F1/GAP-43 mRNA was in fact induced in granule cells and remained elevated above control levels for at least 20 days. The induc tion of F1/GAP-43 mRNA in granule cells was blocked either by MK-801 o r pentobarbital pretreatment. If pentobarbitol was given 55 min, but n ot 90 min, after KA, F1/GAP-43 mRNA was also blocked. Since induction of F1/GAP-43 occurred when pentobarbitol was given 90 min after KA, a 35 min window of activation is required, beyond the initial 55 min, fo r F1/GAP-43 mRNA induction. As both MK-801 and pentobarbital blocked b ehavioral seizures their anti-convulsant action may be important for b locking F1/GAP-43 mRNA induction. Mossy fiber sprouting observed 30 da ys after KA was also blocked when either MK-801 or pentobarbital was g iven prior to KA. These results are consistent with the proposal that protein F1/GAP-43 promotes axonal growth in the adult brain in an inpu t-dependent manner, and may also be of clinical relevance to the molec ular mechanisms underlying structural remodeling in epilepsy.