NEUROPEPTIDE-Y SUPPRESSES EPILEPTIFORM ACTIVITY IN RAT HIPPOCAMPUS IN-VITRO

Neuropeptide Y (NPY) potently inhibits glutamate-mediated synaptic tra nsmission in areas CA1 and CA3 of the rat hippocampus without affectin g other synaptic inputs onto principal cells of the hippocampal format ion, 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 whol e cell patch-clamp recordings from rat hippocampal-entorhinal cortex s lices. Perfusion of the slice with saline that had Mg2+ omitted (0 Mg2 +) or that had picrotoxin (100 mu M) added resulted in brief spontaneo us bursts (SBs) resembling interictal discharges. SE frequency is sign ificantly reduced in both models by 1 mu M NPY and by the Y-2-preferri ng agonists peptide (P)YY3-36 (1 mu M) and 1-4-(6-aminohexanoic acid)- 25-36 ([ahx(5-24)] NPY; 3 mu M). The Y-1-preferring agonist Leu(31)-Pr o(34)NPY (1 mu M) is considerably less potent, but also reduces burst frequency, even in the presence of the selective Y-1 receptor antagoni st GR231118, suggesting the involvement of a different receptor. In ST IB, high frequency stimulus trains to stratum radiatum of area CA2/CA3 result in clonic or tonic-clonic ictaform primary afterdischarges (1 degrees ADs) as well as longer, spontaneous secondary ictaform dischar ges and SBs similar to those in the other models. 1 degrees AD duratio n is greatly reduced or abolished by Y-2-but not Y-1-preferring agonis ts. SBs, although variable, were inhibited by both Y-1 and Y-2 agonist s. 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 applicati on of NPY. SRSEs in pyramidal cells typically occur at 2-4 Hz, are out ward currents when cells are clamped near rest (>100 pA at a holding p otential of -55 mV), reverse between -60 and -70 mV, and are inhibited by 100 mu M picrotoxin. indicating involvement of gamma-aminobutyric acid-A receptors. They are inhibited by blockers of lpha-amino-3-hydro xy-5-methyl-4-isoxazolepropionic acid (AMPA) but not N-methyl-D-aspart ate 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 pyram idal cells. We conclude that NPY, acting predominantly via Y-2 recepto rs, can dramatically inhibit epileptiform activity in three fundamenta lly different in vitro models of epilepsy without affecting endogenous inhibitory activity. The results also provide support for the hypothe sis that endogenous NPY may normally control excitability in the hippo campus and suggest the potential for NPY receptors as targets for anti convulsant therapy.