Y5 Receptors Mediate Neuropeptide Y Actions at Excitatory Synapses in Area CA3 of the Mouse Hippocampus

Abstract

Neuropeptide Y (NPY) is a potent modulator of excitatory synaptic transmission and limbic seizures. NPY is abundantly expressed in the dentate gyrus and is thought to modulate hippocampal excitability via activation of presynaptic Y2 receptors (Y2R). Here we demonstrate that NPY, and commonly used Y2R-preferring (NPY(13-36)) and Y5 receptor (Y5R)-preferring ([D-Trp(32)]NPY and hPP) peptide agonists, evoke similar levels of inhibition at excitatory CA3 synapses in hippocampal slices from wild-type control mice (WT). In contrast, NPYergic inhibition of excitatory CA3 synaptic transmission is absent in mice lacking the Y5R subtype (Y5R KO). In both analyses of evoked population spike activity and spontaneous excitatory postsynaptic synaptic currents (EPSCs), NPY agonists induced powerful inhibitory effects in all hippocampal slices from WT mice, whereas these peptides had no effect in slices from Y5R KO mice. In slices from WT mice, NPY (and NPY receptor-preferring agonists) reduced the frequency of spontaneous EPSCs but had no effect on sEPSC amplitude, rise time, or decay time. Furthermore, NPYergic modulation of spontaneous EPSCs in WT mice was mimicked by bath application of a novel Y5R-selective peptide agonist ([cpp]hPP) but not the selective Y2R agonist ([ahx(5-24)]NPY). In situ hybridization was used to confirm the presence of NPY, Y2, and Y5 mRNA in the hippocampus of WT mice and the absence of Y5R in knockout mice. These results suggest that the Y5 receptor subtype, previously believed to mediate food intake, plays a critical role in modulation of hippocampal excitatory transmission at the hilar-to-CA3 synapse in the mouse.

Mechanisms of Neuropeptide Y, Peptide YY, and Pancreatic Polypeptide Inhibition of Identified Green Fluorescent Protein-Expressing GABA Neurons in the Hypothalamic Neuroendocrine Arcuate Nucleus

“…5C), further suggesting a role for Y 2 receptor subtype in postsynaptic NPY effects. Consistent with this, the specific Y 2 agonist NPY (1 M) (Guo et al, 2002) also induced a consistent hyperpolarization (Fig. 5A, trace 3) of 10.8 Ϯ 3.8 mV (1 M NPY 13-36 ), returning toward control levels after 5-10 min of peptide washout (n ϭ 5) (Fig.…”

“…5C). Preincubation with BIBP3226 (1 M) did not modify 100 nM NPY 13-36 -mediated changes in membrane potential ( p Ͼ 0.05), consistent with activation of a Y 2 receptor (Guo et al, 2002).…”

“…In contrast, the application of the Y 5 agonist [D-Trp 32 ] NPY (1 M) (Inui, 1999;Guo et al, 2002) had a nonsignificant effect on the membrane potential (0.56 Ϯ 1.09 mV compared with control pretreatment levels; n ϭ 5; p ϭ 0.88) (Fig. 5A, trace 4).…”

Estrogen and brain-derived neurotrophic factor (BDNF) in hippocampus: Complexity of steroid hormone-growth factor interactions in the adult CNS

“…This may be due not just to the hilar NPY neurons, but possibly also the NPY neurons of area CA3. Together, they potentially release NPY, which decreases glutamate release from mossy fibers [239,240]. A schematic illustration of the potential for estrogen to exert actions via BDNF and NPY.…”

Plasticity of neuropeptide Y in the dentate gyrus after seizures, and its relevance to seizure-induced neurogenesis

“…This is also suggested by electrophysiological studies, which have shown that NPY influences mossy fiber transmission by a presynaptic mechanism [10]. Both Y2 and Y5 receptors have been implicated in these effects [15,16].…”