The Journal of Neurophysiology Vol. 78 No. 3 September 1997, pp. 1651-1661
Copyright ©1997 The American Physiological Society

Neuropeptide Y Suppresses Epileptiform Activity in Rat Hippocampus In Vitro

Gloria J. Klapstein and William F. Colmers

Department of Pharmacology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

Klapstein, Gloria J. and William F. Colmers. Neuropeptide Y suppresses epileptiform activity in rat hippocampus in vitro. J. Neurophysiol. 78: 1651-1661, 1997. Neuropeptide Y (NPY) potently inhibits glutamate-mediated synaptic transmission in areas CA1 and CA3 of the rat hippocampus without affecting other synaptic inputs onto principal cells of the hippocampal formation, suggesting that its biological role may include the regulation of excitability within the hippocampus. Here we examine NPY's actions in three in vitro models of epilepsy [0 Mg²⁺-, picrotoxin-, and stimulus-train-induced bursting (STIB)] with the use of extracellular and whole cell patch-clamp recordings from rat hippocampal-entorhinal cortex slices. Perfusion of the slice with saline that had Mg²⁺ omitted (0 Mg²⁺) or that had picrotoxin (100 µM) added resulted in brief spontaneous bursts (SBs) resembling interictaldischarges. SB frequency is significantly reduced in both models by 1 µM NPY and by the Y₂-preferring agonists peptide (P)YY_3-36(1 µM) and 1-4-(6-aminohexanoic acid)-25-36 ([ahx^5-24] NPY;3 µM). The Y₁-preferring agonist Leu³¹-Pro³⁴NPY (1 µM) is considerably less potent, but also reduces burst frequency, even in the presence of the selective Y₁ receptor antagonist GR231118, suggesting the involvement of a different receptor. In STIB, high-frequency stimulus trains to stratum radiatum of area CA2/CA3 result in clonic or tonic-clonic ictaform primary afterdischarges (1°ADs) as well as longer, spontaneous secondary ictaform discharges and SBs similar to those in the other models. 1°AD duration is greatly reduced or abolished by Y₂- but not Y₁-preferring agonists. SBs, although variable, were inhibited by both Y₁ and Y₂ agonists. In single and dual whole cell recordings from CA3 pyramidal cells, we frequently observed spontaneous, rhythmic synchronous events (SRSEs) arising after several STIB stimuli. Once established, SRSEs persist in the absence of further stimuli and are insensitive to the application of NPY. SRSEs in pyramidal cells typically occur at 2-4 Hz, are outward currents when cells are clamped near rest (>100 pA at a holding potential of 55 mV), reverse between 60 and 70 mV, and are inhibited by 100 µM picrotoxin, indicating involvement of -aminobutyric acid-A receptors. They are inhibited by blockers of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) but not N-methyl-D-aspartate receptors. Whole cell patch-clamp recordings from interneurons in CA3 after STIB reveal NPY-insensitive, rhythmic, inward AMPA-receptor-mediated currents that are similar in frequency to SRSEs seen in pyramidal cells. We conclude that NPY, acting predominantly via Y₂ receptors, can dramatically inhibit epileptiform activity in three fundamentally different in vitro models of epilepsy without affecting endogenous inhibitory activity. The results also provide support for the hypothesis that endogenous NPY may normally control excitability in the hippocampus and suggest the potential for NPY receptors as targets for anticonvulsant therapy.

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