Adiponectin Functions in Hippocampus

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。

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.