NMDA receptor blockade prevents kainate induction of protein F1/GAP-43 mRNA in hippocampal granule cells and subsequent mossy fiber sprouting in the rat.

Abstract

Granule cells in the adult rat hippocampus do not constitutively express the growth-related axonal protein F1 (a.k.a. B-50, GAP-43, neuromodulin, pp46), yet kainic acid (KA) can induce extensive growth of granule cell axons, the mossy fibers, into the supragranular layer. Does this 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 induction of F1/GAP-43 mRNA in granule cells was blocked either by MK-801 or pentobarbital pretreatment. If pentobarbitol was given 55 min, but not 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, for F1/GAP-43 mRNA induction. As both MK-801 and pentobarbital blocked behavioral seizures their anti-convulsant action may be important for blocking F1/GAP-43 mRNA induction. Mossy fiber sprouting observed 30 days after KA was also blocked when either MK-801 or pentobarbital was given prior to KA. These results are consistent with the proposal that protein F1/GAP-43 promotes axonal growth in the adult brain in an input-dependent manner, and may also be of clinical relevance to the molecular mechanisms underlying structural remodeling in epilepsy.