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The Journal of Neuroscience, August 10, 2005, 25(32):7406-7419; doi:10.1523/JNEUROSCI.1008-05.2005

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

Claudio Acuna-Goycolea,¹ Nobuaki Tamamaki,² Yuchio Yanagawa,^3,4,5 Kunihiko Obata,⁶ and Anthony N. van den Pol¹

¹Department of Neurosurgery, Yale University, New Haven, Connecticut 06520, ²Department of Morphological Neural Sciences, Kumamoto University, Kumamoto 860-8556, Japan, ³Department of Genetic and Behavioral Neuroscience, Gunma University, Maebashi 371-8511, Japan, ⁴Core Research for Evolutional Science and Technology and ⁵Solution-Oriented Research for Science and Technology, Japan Science and Technology Corporation, Kawaguchi 332-0012, Japan, and ⁶Obata Research Unit, RIKEN Brain Science Institute, Wako 351-0198, Japan

The fast inhibitory transmitter GABA is robustly expressed in the arcuate nucleus (ARC) and appears to play a major role in hypothalamic regulation of endocrine function and energy homeostasis. Previously, it has not been possible to record selectively from GABA cells, because they have no defining morphological or physiological characteristics. Using transgenic mice that selectively express GFP (green fluorescent protein) in GAD67 (glutamic acid decarboxylase 67)-synthesizing cells, we identified ARC GABA neurons (n > 300) and used whole-cell recording to study their physiological response to neuropeptide Y (NPY), the related peptide YY_3-36 (PYY_3-36), and pancreatic polypeptide (PP), important modulators of ARC function. In contrast to other identified ARC cells in which NPY receptor agonists were reported to generate excitatory actions, we found that NPY consistently reduced the firing rate and hyperpolarized GABA neurons including neuroendocrine GABA neurons identified by antidromic median eminence stimulation. The inhibitory NPY actions were mediated by postsynaptic activation of G-protein-linked inwardly rectifying potassium (GIRK) and depression of voltage-gated calcium currents via Y₁ and Y₂ receptor subtypes. Additionally, NPY reduced spontaneous and evoked synaptic glutamate release onto GABA neurons by activation of Y₁ and Y₅ receptors. The peptide PYY_3-36, a peripheral endocrine signal that can act in the brain, also inhibited GABA neurons, including identified neuroendocrine cells, by activating GIRK conductances and depressing calcium currents. The endogenous Y₄ agonist PP depressed the activity of GABA-expressing neurons mainly by presynaptic attenuation of glutamate release. Together, these results show that the family of neuropeptide Y modulators reduces the activity of inhibitory GABA neurons in the ARC by multiple presynaptic and postsynaptic mechanisms.

Key words: neuroendocrine; glutamate; GABA; mediobasal hypothalamus; feeding; neuropeptide Y

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Received March 15, 2005; revised June 3, 2005; accepted June 23, 2005.

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