The anti‐epileptic actions of neuropeptide Y in the hippocampus are mediated by Y₂ and not Y₅ receptors

Abstract

Neuropeptide Y (NPY) potently inhibits glutamate release and seizure activity in rodent hippocampus in vitro and in vivo, but the nature of the receptor(s) mediating this action is controversial. In hippocampal slices from rats and several wild-type mice, a Y2-preferring agonist mimicked, and the Y2-specific antagonist BIIE0246 blocked, the NPY-mediated inhibition both of glutamatergic transmission and of epileptiform discharges in two different slice models of temporal lobe epilepsy, stimulus train-induced bursting (STIB) and 0-Mg2+ bursting. Whereas Y5 receptor-preferring agonists had small but significant effects in vitro, they were blocked by BIIE0246, and a Y5 receptor-specific antagonist did not affect responses to any agonist tested in any preparation. In slices from mice, NPY was without effect on evoked potentials or in either of the two slice seizure models. In vivo, intrahippocampal injections of Y2- or Y5-preferring agonists inhibited seizures caused by intrahippocampal kainate, but again the Y5 agonist effects were insensitive to a Y5 antagonist. Neither Y2- nor Y5-preferring agonists affected kainate seizures in mice. A Y5-specific antagonist did not displace the binding of two different NPY ligands in WT or mice, whereas all NPY binding was eliminated in the mouse. Thus, we show that Y2 receptors alone mediate all the anti-excitatory actions of NPY seen in the hippocampus, whereas our findings do not support a role for Y5 receptors either in vitro or in vivo. The results suggest that agonists targeting the Y2 receptor may be useful anticonvulsants.

Dopamine modulates synaptic plasticity in dendrites of rat and human dentate granule cells

“…Rat experiments were performed in hippocampal slices from 3-to 5-wk-old male (or female where indicated) rats as described previously (48). Rats were decapitated and the brains were removed and placed into an ice-cold (0-4°C) slicing solution (SI Materials and Methods).…”

Effect of neuropeptide Y Y2 receptor deletion on emotional stress‐induced neuronal activation in mice

“…Y2 receptors are thought to be mainly presynaptic receptors mediating an inhibition of transmitter release by inhibiting Ca 2+ influx through N-type channels as demonstrated in the hippocampus in vitro and in vivo (El Bahh et al, 2005). Depending on the nerve terminal on which they are located, they may reduce GABA, NPY, glutamate, or noradrenaline release (Chen and van den Pol, 1996;Greber et al, 1994;Klapstein and Colmers, 1992;Martire et al, 1993;Sun et al, 2001).…”

Receptor Subtype-specific Docking of Asp6.59 with C-terminal Arginine Residues in Y Receptor Ligands

“…Y 1 R and Y 4 R require the complete N terminus of the ligand (15,19,20). Y 5 R accepts peptides with the deletion of the first amino acid (21), and Y 2 R even binds significantly shorter peptides (NPY ) or centrally truncated analogs ([Ahx [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] ]NPY) with only minor effects on affinity (19,22). However, the C-terminal pentapeptide of all natural ligands was identified as an essential region for binding to all YRs (23,24), and these residues of the ligand C terminus seem to represent a core contact domain.…”

“…All members are C-terminally amidated polypeptides consisting of 36 amino acids (1) and are involved in multiple physiological processes, including memory retention (2, 3), feeding behavior (4,5), control of blood pressure (6,7), and seizure (8).…”