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

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Abstract
Coogan, Andrew N., Deirdre M. O'Leary, and John J. O'Connor. P42/44 MAP kinase inhibitor PD98059 attenuates multiple forms of synaptic plasticity in rat dentate gyrus in vitro. J. Neurophysiol. 81: 103–110, 1999. The effects of the specific p42/44 mitogen-activated protein (MAP) kinase cascade inhibitor, PD98059, were investigated on three types of long-term potentiation (LTP) in the medial perforant path of the rat dentate gyrus in vitro: 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) agonist (S)-dihydrophenylglycine (S-DHPG) for 2 min (DHPG-LTP). Bath perfusion of PD98059 (50 μM) for 1 h inhibited HFS-LTP (111 ± 5%, mean ± SE, at 90 min posttetanus in test slices compared with 144 ± 5% in control slices; n = 6–7). Concentrations of 10 and 20 μM PD98059 had no effect on HFS-LTP ( n = 6). PD98059 (50 μM) had no effect on the isolated N-methyl-d-aspartate excitatory postsynaptic potential (NMDA-EPSP) or on the maintenance phase of HFS-LTP. PD98059 (50 μM) 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. Bath application of (S)-DHPG (40 μM) for 2 min gave rise to a potentiation of the EPSPs slope (148 ± 4% at 1 h post-DHPG wash out; n = 5). Pretreatment of slices with PD98059 (50 μM) 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 wash out; n = 6) was found to be both d-2-amino-5-phosphonopentanoic acid (d-AP5; 100 μM) and nifedipine (20 μM) independent. However, the T type voltage-dependent calcium-channel blocker, NiCl2 (50 μM), completely inhibited the observed potentiation. The mGluR receptor antagonist α-methyl-4-carboxy-phenyl glycine (MCPG; 100 μM) and PD98059 (50 μM) caused a complete 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-dependent and two forms of NMDA-independent LTP in the dentate gyrus.