Abstracts

RATIONALE: Neuropeptide Y (NPY), a widely expressed neuromodulator, inhibits synaptic excitation in hippocampal area CA3. In the rat hippocampus, this effect was shown to be mediated by activation of Y2 NPY receptors [J. Neurophys. 76:3159, 1996]. Because we recently found that NPY's antiepileptic effects are mediated by a Y5 receptor in the mouse [PNAS 96:13518, 1999], we studied the site of action of NPY in hippocampal slices from Y5 receptor knockout (Y5rx KO) and wild-type control (WT) mice. METHODS: Whole-cell voltage-clamp recordings were obtained from visualized CA3 pyamidal cells in acute hippocampal slices (P10-P20). Slices were bathed in nACSF supplemented with 100 ?M bicuculline to block inhibitory postsynaptic currents caused by activation of GABAA receptors. RESULTS: Spontaneous excitatory postsynaptic currents (EPSCs) were recorded from CA3 pyramidal neurons at holding potentials between -70 and -90 mV. EPSCs reversed around 0 mV and were blocked by the addition of 1 mM kynurenate or 50 ?M APV/10 ?M CNQX to the bathing medium. In slices from WT mice (n = 10), bath application of 1 ?M NPY significantly reduced the frequency of spontaneous EPSCs. NPY application did not affect EPSC amplitude, time constant of the rising phase, or time constant of decay. Similar effects were observed during bath application of 1 ?M peptide YY (NPY analog), 1 ?M NPY13-36 (Y2 receptor-preferring agonist) or 1 ?M hPP (Y5 receptor-preferring agonist). NPY also inhibited CA3 EPSCs evoked by mossy fibre stimulation. In slices from Y5rx KO mice (n = 12), spontaneous EPSCs were not altered during bath application of NPY, PYY, NPY13-36 or hPP. Subsequent application of kynurenate or APV/CNQX inhibited EPSCs in these slices. Similarly, evoked EPSCs were not inhibited during application of NPY or peptide analogs. CONCLUSIONS: Our results support the hypothesis that NPY inhibits synaptic excitation of CA3 pyramidal neurons. In contrast to studies performed in rats, our studies suggest that NPY's inhibitory actions on excitatory neurotransmission are mediated by a Y5 receptor. [Support: March of Dimes, Lucille Packard CHI, and Sandler Family Supporting Foundation].