THE NITRIC-OXIDE SYNTHASE INHIBITOR, N-MONOMETHYL-L-ARGININE BLOCKS INDUCTION OF A LONG-TERM POTENTIATION-LIKE PHENOMENON IN RAT MEDIAL FRONTAL CORTICAL-NEURONS IN-VITRO

1. Nitric oxide has been implicated in the production of long-term dep ression (LTD) in the cerebellum and in the production of long-term pot entiation (LTP) and LTD in the hippocampus. We now provide evidence of its involvement in the induction of long-term synaptic potentiation i n in vitro slices in the cerebral cortex of the rat. 2. Intracellular recordings were made from layer V neurons in the medial frontal cortex , and excitatory synaptic potentials (EPSPs) were evoked by electrical stimulation of layers II/III. Tetanic stimulation of this pathway may induce LTD or LTP or no change at these synapses. First we establishe d experimental conditions under which a long lasting potentiation coul d be induced with a high incidence (>60%), namely perfusion of slices with 1 muM bicuculline methiodide, second the use of increased shock d uration in the tetanic conditioning stimuli, third and most important the addition of QX-314 to the microelectrode to reduce potassium condu ctances. Because the potentiation of the mean EPSP slope was significa ntly greater than the control at 40-min postconditioning, but was decl ining throughout this period, we refer to it for brevity as LTP, but s trictly class it as an LTP-like phenomenon. 3. The nitric oxide (NO) s ynthase inhibitor interfered with the production of LTP. In the contro l group of neurons (n = 13) the mean depolarizing slope of the EPSP at 30-min post-conditioning was 142.7 +/- 2% (mean +/- SE) of the presti mulation control. In contrast, in the group of cells (n = 12) in slice s preincubated with the nitric oxide synthase inhibitor, N-monomethyl- L-arginine (L-NMMA) at 100 muM for >45 min, the mean slope of the EPSP at 30-min post-tetanus was 109% (+/- 1.7%). The difference between th e control and the L-NMMA groups was significant at P < 0.01 (t test, t wo-tailed). The probability of induction of LTP was also greatly reduc ed by the synthase inhibitor while the probability of the conditioning producing no change or LTD was increased and that of producing LTD wa s also increased. The change in incidence of LTP was significantly dif ferent between the two groups at P < 0.05 (chi2 test). 4. Following un successful attempts to induce long-term potentiation in the presence o f the nitric oxide synthase inhibitor, in five slices the L-NMMA was r eplaced with perfusate containing the substrate L-arginine. Subsequent ly, long-term potentiation was induced in 2 of the 5 slices, thus reve rsing the effect of blockade in those two cells. 5. We conclude that n itric oxide synthase is involved in the production of a LTP like chang e at synapses on layer V cells in medial frontal cortex and implicate nitric oxide as a transcellular messenger in synaptic plasticity in th e neocortex, as in the cerebellum and hippocampus.