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、稳定性和功能方面的重要性。T-cadherin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-linked cadherin型粘附蛋白。我们在心血管系统的研究证实了T-钙粘蛋白是APN功能的生理关键受体/共受体（Hebbard et al. 2008; Denzel et al. 2010）。人类CDH13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，人类病例对照研究已经将附近的CDH13 snp簇与注意缺陷多动和共病神经精神疾病联系起来。在阐明T-cadherin在cdh13缺陷小鼠神经系统中的功能时，我们发现了cdh13缺陷小鼠的海马突触功能和可塑性的缺陷，这表现在cdh13缺陷主神经元的树突棘改变中。t -钙粘蛋白是由gaba能中间神经元在不表达t -钙粘蛋白的主要锥体神经元树突上突触表达的。关于这一问题的一个重要发现是，脂联素（APN）在接受表达T-cadherin的中间神经元输入的海马锥体细胞中表达，而脂联素在遗传上需要T-cadherin来调节外周功能。综上所述，这些发现提出了一个有趣的假设，即APN是t -钙粘蛋白信号通路的一部分，该通路调节海马体中的电路，对联想记忆行为有深远的影响，因为Cdh13-KO小鼠在恐惧和奖励条件反射测试中表现出显著的损伤。在这个探索性的提议中，我们将基因测试APN在海马突触功能中与t -钙粘蛋白相关的作用。

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.