Long-term potentiation in dentate gyrus of the rat is inhibited by the phosphoinositide 3–kinase inhibitor, wortmannin

Abstract

The pivotal role of inositol phospholipids in cell signalling has been placed centre-stage again with the recognition that phosphoinositide (PI) 3–kinase is implicated in several cellular processes. Stimulation of PI–3 kinase requires activation of the 85 kD regulatory subunit which relies on tyrosine phosphorylation, one consequence of which is activation of the 110 kD catalytic subunit. In this study, we have investigated the role of PI 3–kinase in the expression of long-term potentiation (LTP) in perforant path-granule cell synapses of the rat. We report that intracerebroventricular injection of wortmannin inhibited expression of LTP, though it did not affect the early change in the synaptic response. Activation of PI 3–kinase was enhanced in tetanized tissue prepared from dentate gyrus, compared with untetanized tissue, but this effect was inhibited in tissue prepared from wortmannin-pretreated rats. LTP was associated with increased glutamate release, as previously described, but this effect was also inhibited in tissue prepared from wortmannin-pretreated rats. The results presented demonstrate that wortmannin also exerted an inhibitory effect on KCl-stimulated glutamate release and calcium influx in hippocampal synaptosomes in vitro. The evidence presented is consistent with the hypothesis that PI 3–kinase activation, possibly by NGF, plays a role in expression of LTP in dentate gyrus.