Adiponectin Functions in Hippocampus

脂联素在海马中的功能

• 批准号: 8685062
• 负责人: BARBARA RANSCHT
• 金额: $ 29.25万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-03 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685062
• 关键词: 16q24; Adhesions; Adipocytes; Affect; Alleles; Area; Attention; Attention deficit hyperactivity disorder; Back; Behavior; Behavioral; Binding; Blood - brain barrier anatomy; Blood Circulation; CDH13 gene; Cadherins; Cardiovascular system; Case-Control Studies; Cell Adhesion Molecules; Cells; Cytoplasmic Granules; Data; Defect; Dendrites; Dendritic Spines; Disease; Exons; Fright; Functional disorder; Genes; H-Cadherin; Hippocampus (Brain); Homeostasis; Human; Human Chromosomes; Hyperactive behavior; Immunohistochemistry; Impairment; Inflammation; Interneurons; Laboratories; Link; Lipids; Memory; Mental disorders; Metabolic; Modeling; Morphology; Mus; Mutant Strains Mice; Mutation; Nervous system structure; Neuraxis; Neurons; Outcome; Pathway interactions; Pattern; Physiological; Presynaptic Terminals; Proteins; Psyche structure; Pyramidal Cells; Research Design; Rewards; Role; Signal Pathway; Signal Transduction; Slice; Stimulus; Synapses; Synaptic plasticity; Testing; Time; Transcript; Ursidae Family; Vertebral column; Work; adiponectin; base; conditioning; cytokine; genome wide association study; genome-wide; glucose metabolism; hippocampal pyramidal neuron; mutant; neural circuit; neuropsychiatry; protein expression; public health relevance; receptor; response; synaptic function; synaptogenesis

DESCRIPTION (provided by applicant): A growing body of evidence indicates the importance of cell adhesion molecules in regulating synapse formation, stability and function in the central nervous system (CNS). T-cadherin encoded by the Cdh13 gene, is a unique GPI-linked cadherin type adhesion protein discovered and extensively studied in our laboratory. Our work in the cardiovascular system established T- cadherin as a physiological key receptor/co-receptor for APN functions (Hebbard et al. 2008; Denzel et al 2010). Mutations in the human CDH13 gene have been associated with hypoadiponectemia and cardiovascular dysfunctions. In the nervous system, human case- control studies have linked clusters of nearby CDH13 SNPs to attention deficit hyperactivity and comorbid neuropsychiatric disorders. Elucidating functions for T-cadherin in the nervous system in Cdh13-deficient mice, we discovered defects in hippocampal synaptic function and plasticity manifesting in dendritic spine changes of Cdh13-deficient principal neurons. T-cadherin is expressed by GABAergic interneurons synapsing on dendrites of the principal pyramidal neurons that do not express T-cadherin. A major discovery that could bear on this issue is the fact that Adiponectin (APN), genetically requiring T-cadherin for regulating functions in the periphery, is expressed by hippocampal pyramidal cell receiving inputs from T-cadherin- expressing interneurons. In combination, these findings raise the intriguing hypothesis that APN is part of the T-cadherin signaling pathway that modulates circuits in the hippocampus, with profound affects on associative memory behaviors as Cdh13-KO mice show significant impairments in fear- and reward-based conditioning tests. In this exploratory proposal, we will genetically test the role of APN in hippocampal synaptic functions in relation to T-cadherin.

描述（由申请人提供）：越来越多的证据表明细胞粘附分子在调节中枢神经系统（CNS）突触形成、稳定性和功能中的重要性。 T-钙粘蛋白由Cdh13基因编码，是我们实验室发现并广泛研究的一种独特的GPI连接钙粘蛋白型粘附蛋白。我们在心血管系统方面的工作确立了 T-钙粘蛋白作为 APN 功能的生理关键受体/辅助受体（Hebbard 等人，2008 年；Denzel 等人，2010 年）。人类 CDH13 基因突变与低脂联血症和心血管功能障碍有关。在神经系统中，人类病例对照研究已将附近的 CDH13 SNP 簇与注意力缺陷多动和共病神经精神疾病联系起来。在阐明 Cdh13 缺陷小鼠神经系统中 T-钙粘蛋白的功能时，我们发现了 Cdh13 缺陷主要神经元树突棘变化中表现出的海马突触功能和可塑性缺陷。 T-钙粘蛋白由在不表达T-钙粘蛋白的主要锥体神经元的树突上突触的GABA能中间神经元表达。可能与这个问题相关的一个重大发现是，脂联素 (APN) 在遗传上需要 T-钙粘蛋白来调节外周功能，它是由海马锥体细胞表达的，该细胞接收来自表达 T-钙粘蛋白的中间神经元的输入。综合起来，这些发现提出了一个有趣的假设，即 APN 是调节海马回路的 T-钙粘蛋白信号通路的一部分，对联想记忆行为具有深远的影响，因为 Cdh13-KO 小鼠在基于恐惧和奖励的条件反射测试中表现出显着的损伤。在这个探索性提案中，我们将从基因角度测试 APN 在海马突触功能中与 T-钙粘蛋白相关的作用。