Acuna-Goycolea Claudio, Tamamaki Nobuaki, Yanagawa Yuchio, Obata Kunihiko, van den Pol Anthony N
Department of Neurosurgery, Yale University, New Haven, Connecticut 06520, USA.
J Neurosci. 2005 Aug 10;25(32):7406-19. doi: 10.1523/JNEUROSCI.1008-05.2005.
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.
快速抑制性神经递质γ-氨基丁酸（GABA）在弓状核（ARC）中大量表达，并且似乎在下丘脑对内分泌功能和能量稳态的调节中发挥主要作用。以前，无法从GABA能细胞中进行选择性记录，因为它们没有明确的形态学或生理学特征。利用在合成GAD67（谷氨酸脱羧酶67）的细胞中选择性表达绿色荧光蛋白（GFP）的转基因小鼠，我们鉴定出ARC中的GABA能神经元（n>300），并使用全细胞记录来研究它们对神经肽Y（NPY）、相关肽YY（3-36）（PYY（3-36））和胰多肽（PP）的生理反应，这些都是ARC功能的重要调节因子。与其他已鉴定的ARC细胞不同，据报道NPY受体激动剂在这些细胞中产生兴奋作用，我们发现NPY持续降低放电频率并使GABA能神经元超极化，包括通过逆向正中隆起刺激鉴定的神经内分泌GABA能神经元。NPY的抑制作用是由G蛋白偶联内向整流钾通道（GIRK）的突触后激活以及通过Y1和Y2受体亚型抑制电压门控钙电流介导的。此外，NPY通过激活Y1和Y5受体减少了GABA能神经元上的自发性和诱发性突触谷氨酸释放。肽PYY（3-36）是一种可在大脑中发挥作用的外周内分泌信号，它也通过激活GIRK电导和抑制钙电流来抑制GABA能神经元，包括已鉴定的神经内分泌细胞。内源性Y4激动剂PP主要通过突触前谷氨酸释放的减弱来降低表达GABA的神经元的活性。总之，这些结果表明神经肽Y调节因子家族通过多种突触前和突触后机制降低了ARC中抑制性GABA能神经元的活性。
