Activation of tyrosine receptor kinase plays a role in expression of long-term potentiation in the rat dentate gyrus

Long-term potentiation (LTP) in perforant path-granule cell synapses has be en shown to be accompanied by an increase in glutamate release. The objecti ve of this study was to examine the possibility that nerve growth factor (N GF), by activating tyrosine kinase, modulates glutamate release and, theref ore, contributes to expression of LTP in dentate gyrus. The data indicate t hat NGF, in the presence of trans-1-aminocyclopentyl-1,3-dicarboxylate (ACP D), enhanced KCI-stimulated release and KCI-stimulated calcium influx in vi tro and that these effects were blocked by the tyrosine receptor kinase (tr k) inhibitor tyrphostin AG879. The data also indicate that NGF increased ph osphorylation of trkA and the mitogen-activated protein kinase extracellula r signal-regulated kinase (ERK) in dentate gyrus in vitro. In addition to i ts effects in vitro, tyrphostin AG879 inhibited the expression of LTP in pe rforant path-granule cell synapses and the accompanying increase in transmi tter release. Analysis of phosphorylation of the two tyrosine kinase substr ates trkA and ERK in synaptosomes prepared from untetanized and tetanized d entate gyrus revealed that LTP was associated with increased phosphorylatio n of both proteins; no evidence of such a change was observed in either tet anized or untetanized tissue prepared from tyrphostin-pretreated rats. Thes e findings are consistent with the hypothesis that NGF, by interacting with trkA, triggers a sequence of tyrosine kinase-dependent phosphorylation ste ps that modulate glutamate release and calcium influx and impact on express ion of LTP in dentate gyrus. (C) 1999 Wiley-Liss, Inc.