Analysis of the presynaptic signalling mechanisms underlying the inhibition of LTP in rat dentate gyrus by the tyrosine kinase inhibitor, genistein

✍ Scribed by Marina Lynch

• Publisher: John Wiley and Sons
• Year: 2004
• Tongue: English
• Weight: 45 KB
• Volume: 14
• Category: Article
• ISSN: 1050-9631
• DOI: 10.1002/hipo.10147

✦ Synopsis

This study was one of a series designed to analyse signalling events in the hippocampus after induction of long-term potentiation (LTP). The specific purpose was to further analyse changes associated with tyrosine kinase activation after earlier observations. Among the earlier observations were the findings that tyrphostin AG879, a Trk inhibitor, which blocks downstream activation of extracellular signal-regulated kinase (ERK), inhibits LTP (Maguire et al., 1999) and KCl-stimulated glutamate release (Maguire et al., 1999). These effects were also observed after treatment with PD98059 (Mc-Gahon et al., 1999;Gooney et al., 2002), and the inhibitory effect of tyrphostin AG879 and PD98059 on glutamate release in vitro was mimicked by UO126 (Gooney and Lynch, 2001). Interestingly, calcium influx into hippocampal synaptosomes, which was enhanced by nerve growth factor (NGF) and trans1-aminocyclopentyl-1,3-dicarboxylate (ACPD), was also inhibited by tyrphostin AG879. With respect to evidence indicating a role for tyrosine kinase in LTP, specifically in modulating presynaptic events, we have reported that among the substrates that exhibit increased tyrosine phosphorylation is the synaptic vesicle protein, synaptophysin (Mullany and Lynch, 1998); this provides direct evidence of a presynaptically located response to LTP-induced activation of tyrosine kinase. Significantly this latter effect was prevented by treatment of rats with tyrphostin AG879. It is indeed the case that genistein exerts effects other than inhibition of tyrosine kinase but, given the series of experiments referred to above and the findings of a great number of other investigators to which our article refers, I would suggest that, on balance, the data appear to support our conclusion.