Function of galanin receptor subtypes in the hippocampus

描述（由申请人提供）：甘丙肽，一种广泛表达的神经肽， 当脑室内应用时， 癫痫发作活动，并影响性活动和进食行为。这些 至少有三种已知的G蛋白发挥不同的药理作用， 偶联受体：GALR 1、GALR 2和GALR 3。甘丙肽的体内作用具有 通过使用甘丙肽和一些高亲和性嵌合肽， 甘丙肽拮抗剂M15、M35和M40。这些配体缺乏 受体亚型的选择性，因此，贡献的具体甘丙肽 受体亚型对甘丙肽的多种体内作用的影响尚不清楚。的 与不同甘丙肽的激活偶联的第二信使系统 已经在转染的非神经元细胞中研究了受体亚型， 同样的信号传导是否发生在海马神经元表达 这些受体有自己的G蛋白在这项研究中，我们希望 确定在CA 1的锥体细胞中表达的GALR 1的贡献，以及 GALR 2在齿状回颗粒细胞中表达， 这些神经元。我们将研究CREB和MAPK通路和海马 兴奋性，包括齿状回和CA 1区域的LTP， 甘丙肽会显著降低血压在缺乏受体亚型特异性 为了确定特定甘丙肽受体亚型的作用，我们将 利用GALR 1（-/-）转基因小鼠和体内下调GALR 1 通过细胞穿透肽核酸（PNA）类型和GALR 2表达 反义寡核苷酸应用于icv。最后，研究了 突触前甘丙肽受体调节去甲肾上腺素（NE），谷氨酸和 海马体中乙酰胆碱（ACh）的释放将在 微透析实验我们假设甘丙肽作用于GALR 1， GALR 2受体抑制海马兴奋性， 癫痫发作阈值和认知功能。预计结果将 形成理解不同甘丙肽受体作用的基础 亚型，并将这些甘丙肽受体亚型定义为假定的 认知能力增强药物的药物靶点。而且这些 甘丙肽受体亚型参与调节 大脑中的肾上腺素能和去甲肾上腺素能细胞，以及关于 它们在海马体中的作用机制可能有助于理解 它们在这些单胺能系统和抑郁症中的作用。也因为 甘丙肽已被证明具有抗癫痫作用，了解这是如何 肽调节癫痫发作可能具有临床应用， 癫痫

DESCRIPTION (provided by applicant): Galanin, a broadly expressed neuropeptide, when applied intracerebroventricularly impairs cognitive performance, dampens seizure activity, and affects sexual activity and feeding behaviors. These diverse pharmacological effects are exerted by at least three known G protein coupled receptors: GALR1, GALR2, and GALR3. The in vivo effects of galanin have been determined by using the peptide galanin and some high affinity chimeric galanin antagonists, M15, M35 and M40, which we introduced. These ligands lack receptor subtype selectivity, and thus the contribution of the specific galanin receptor subtypes to the multiple in vivo effects of galanin is not known. The second messenger systems coupled to activation of the different galanin receptor subtypes have been studied in transfected non-neuronal cells, leaving in doubt whether the same signaling occurs in hippocampal neurons expressing these receptors with their own set of G-proteins. In this study we wish to determine the contribution of GALR1, expressed in pyramidal cells of CA1, and of GALR2, expressed in the granule cells in the dentate gyrus, to signaling in these neurons. We will examine CREB and MAPK pathways and hippocampal excitability, including LTP in the dentate gyrus and CA1 regions, which are markedly depressed by galanin. In the absence of receptor subtype-specific ligands, to determine the roles of specific galanin receptor subtypes we will utilize the GALR1 (-/-) transgenic mice and in vivo down regulation of GALR1 and GALR2 expression by cell penetrating peptide nucleic acid (PNA) type antisense oligonucleotides applied icv. Finally, the subtype(s) specificity of presynaptic galanin receptors that regulate noradrenaline (NE), glutamate and acetylcholine (ACh) release in the hippocampus will be addressed in microdialysis experiments. We hypothesize that galanin acting at GALR1 and GALR2 receptors suppresses hippocampal excitability with consequences for seizure threshold and cognitive function. It is expected that the results will form the basis for understanding the role of different galanin receptor subtypes in cognition, and define these galanin receptor subtypes as putative drug targets for cognitive performance-enhancing drugs. Furthermore, these galanin receptor subtypes participate in the regulation of the firing of serotonergic and noradrenergic cells in the brain, and information regarding their mechanism of action in the hippocampus may contribute to understanding their effects in these monoaminergic systems, and in depression. Also, because galanin has been shown to have anti-epileptic actions, understanding how this peptide regulates seizures could have clinical applications in the treatment of epilepsy.