P42/44 MAP kinase inhibitor PD98059 attenuates multiple forms of synaptic plasticity in rat dentate gyrus in vitro

The effects of the specific p42/44 mitogen-activated protein (MAP) kinase c ascade inhibitor, PD98059, were investigated on three types of long-term po tentiation (LTP) in the medial perforant path of the rat dentate gyms in vi tro: LTP induced by 1) high-frequency stimulation (HFS-LTP), 2) application for 10 min of the K+ channel blocker, tetraethylammonium chloride (TEA-LTP ), and 3) application of the metabotropic glutamate receptor (mGluR) agonis t (S) -dihydrophenylglycine (S-DHPC) for 2 min (DHPG-LTP). Bath perfusion o f PD98059 (50 mu M) for 1 h inhibited HFS-LTP (111 +/- 5%, mean +/- SE, at 90 min posttetanus in test slices compared with 144 +/- 5% in control slice s; n = 6-7). Concentrations of 10 and 20 mu M PD98059 had no effect on HFS- LTP (n = 6). PD98059 (50 mu M) had no effect on the isolated N-methyl-D-asp artate excitatory postsynaptic potential (NMDA-EPSP) or on the maintenance phase of HFS-LTP. PD98059 (50 mu M) did not affect paired-pulse depression (PPD; interstimulus intervals of 10 and 100 ms) of synaptic transmission as is typically observed in the medial perforant path of the dentate gyrus. B ath application of (S)-DHPG (40 mu M) for 2 min gave rise to a potentiation of the EPSPs slope (148 +/- 4% at 1 h post-DHPG wash out; n = 5). Pretreat ment of slices with PD98059 (50 mu M) inhibited the DHPG-LTP (98 +/- 3% at 1 h post-DHPG wash out; n = 5). The TEA-LTP (125 +/- 4% at 1 h post-TEA was h out; n = 6) was found to be both D-2-amino-5-phosphonopentanoic acid(D-AP S; 100 mu M) and nifedipine (20 mu M) independent. However, the T type volt age-dependent calcium-channel blocker, NiCl2 (50 mu M), completely inhibite d the observed potentiation. The mGluR receptor antagonist alpha-methyl-4-c arboxy-phenyl glycine (MCPG; 100 mu M) and PD98059 (50 mu M) caused a compl ete block of the TEA-LTP. These data show for the first time an involvement of the p42/44 MAP kinase in the induction and expression of both an NMDA-d ependent and two forms of NMDA-independent LTP in the dentate gyrus.