The Journal of Neurophysiology Vol. 81 No. 1 January 1999, pp. 103-110
Copyright ©1999 The American Physiological Society

P42/44 MAP Kinase Inhibitor PD98059 Attenuates Multiple Forms of Synaptic Plasticity in Rat Dentate Gyrus In Vitro

Andrew N. Coogan, Deirdre M. O'Leary, and John J. O'Connor

Department of Human Anatomy and Physiology, University College, Earlsfort Terrace, Dublin 2, Ireland

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 -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.

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