Activation of p42 mitogen-activated protein kinase by arachidonic acid andtrans-1-amino-cyclopentyl-1,3-dicarboxylate impacts on long-term potentiation in the dentate gyrus in the rat: Analysis of age-related changes

Maintenance of long-term potentiation in perforant path-granule cell synaps es is associated with an increase in glutamate release, which we have sugge sted relies on an interaction between arachidonic acid and the metabotropic glutamate receptor agonist, trans-1-amino-cyclopentyl-1,3-dicarboxylate (A CPD). Evidence suggests that this interaction is dependent on stimulation o f tyrosine kinase, which phosphorylates and activates phospholipase Cy. In this study, we demonstrate that arachidonic acid and ACPD stimulate tyrosin e phosphorylation of a protein of about 40,000 mel. wt and further analysis , using a specific antibody, suggested that this may be extracellular signa l-regulated kinase, one member of the family of mitogen-activated protein k inases. Activity of extracellular signal-regulated kinase was increased by arachidonic acid and ACPD in vitro, but it was also increased by induction of long-term potentiation in perforant path-granule cell synapses. A role f or extracellular signal-regulated kinase in long-term potentiation was supp orted by the observation that expression of long-term potentiation, as well as the associated increases in endogenous glutamate release and extracellu lar signal-regulated kinase activation, were inhibited by pretreatment with the mitogen-activated protein kinase inhibitor, PD98059, while PD98059 pre treatment inhibited the interaction between arachidonic acid and ACPD on gl utamate release. An age-related decrease in extracellular signal-regulated kinase activity was observed in the dentate gyms, and there was no evidence of increased extracellular signal-regulated kinase activity or endogenous glutamate release in tissue prepared from aged rats in which long-term pote ntiation was compromised. The evidence is consistent with the view that increased activation of extra cellular signal-regulated kinase plays a role in long-term potentiation, an d that activation of this kinase relies on the interaction between arachido nic acid and ACPD. (C) 1999 IBRO. Published by Elsevier Science Ltd.