Antiepileptic Actions of Neuropeptide Y in the Mouse Hippocampus Require Y5 Receptors


  • Scott C. Baraban

    1. Department of Neurological Surgery and The Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, California, U.S.A.
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Address correspondence and reprint requests to Dr. S. C. Baraban at Box 0520, Department of Neurological Surgery, 513 Parnassus Avenue, UCSF, San Francisco, CA 94143, U.S.A. E-mail:


Summary:  Purpose: Recent evidence suggests an antiepileptic role for neuropeptide Y (NPY) in the central nervous system. The precise receptor subtypes mediating the inhibitory actions of NPY in the hippocampal formation, however, remain unclear. In vitro studies suggest a role for Y2 receptors in modulating excitatory hippocampal synaptic transmission and epileptiform discharge. In vivo studies implicate Y5 receptors. Here we used pharmacologic tools and Y5-receptor knockout mice to examine the role of Y5 receptors in mediating the antiexcitatory and antiepileptic actions of NPY in the hippocampal formation.

Methods: Hippocampal slices were obtained from age-matched wild-type (WT; 129 s3/svimj) and Y5-receptor knockout (Y5R KO) mice generated on the same background strain. Extracellular or whole-cell voltage-clamp recordings were obtained in area CA3 pyramidale. Evoked population spikes or excitatory postsynaptic currents were monitored during bath application of NPY, NPY13-36, or human pancreatic polypeptide (hPP). In some slices, zero-magnesium cerebrospinal fluid (CSF) was used to evoke spontaneous epileptiform discharges.

Results: NPY and NPY agonists with preference for either Y2 (NPY13-36) or Y5 (hPP) receptor subtypes caused a significant reduction in population spike and excitatory postsynaptic current (EPSC) amplitudes in slices from WT mice. NPY (and NPY agonists) also suppressed zero-magnesium epileptiform burst discharge in slices from WT mice. In contrast, bath application of NPY, NPY13-36, or hPP had no effect in slices from Y5R KO mice.

Conclusions: NPY modulates excitatory synaptic transmission and inhibits limbic seizure activity in the mouse hippocampus. The antiepileptic actions of NPY, in the mouse, appear to require activation of hippocampal Y5 receptors.