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Adiponectin Functions in Hippocampus

脂联素在海马中的功能

基本信息

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
项目类别：
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

项目摘要

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。由Cdh 13基因编码的T-cadherin是我们实验室发现并广泛研究的一种独特的GPI连锁的钙粘蛋白型粘附蛋白。我们在心血管系统中的工作确立了T-钙粘蛋白作为APN功能的生理关键受体/共受体（Hebbard et al. 2008; Denzel et al 2010）。人类CDH 13基因突变与低脂血症和心血管功能障碍有关。在神经系统中，人类病例对照研究将附近的CDH 13 SNP簇与注意力缺陷多动和共病神经精神障碍联系起来。阐明功能的T-钙粘蛋白在Cdh 13缺陷小鼠的神经系统中，我们发现缺陷的海马突触功能和可塑性表现在树突棘的Cdh 13缺陷的主要神经元的变化。T-钙粘蛋白由与不表达T-钙粘蛋白的主要锥体神经元的树突突触的GABA能中间神经元表达。一个重大发现，可能承担这个问题是脂联素（APN），在遗传上需要T-钙粘蛋白调节功能的周边，表达海马锥体细胞接受输入的T-钙粘蛋白表达的中间神经元。结合起来，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，对关联记忆行为有深远的影响，因为Cdh 13-KO小鼠在基于恐惧和奖励的条件反射测试中表现出显著的损伤。在这个探索性的建议，我们将在遗传学上测试的作用，APN在海马突触功能的T-钙粘蛋白。