Division of Neuroanatomy, Department of Neuroscience, Yamaguchi University, Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
Neuroscience. 2012 May 17;210:67-81. doi: 10.1016/j.neuroscience.2012.02.029. Epub 2012 Feb 22.
Huntingtin-associated protein 1 (HAP1) is a neural huntingtin interactor that is widely expressed as a core molecule of the stigmoid body (a neurocytoplasmic inclusion) in the limbic and hypothalamic regions and has putative protective functions against some neurodegenerative diseases (HAP1 protection hypothesis). Although HAP1 has been reported to be intimately associated with several steroid receptors, HAP1-immunoreactive (HAP1-ir) cells remain to be identified in the hippocampus, which is one of the major steroidal targets. In this study, we determined the distribution of hippocampal HAP1-ir cells in light and fluorescence microscopy and characterized their morphological relationships with steroid receptors, markers of adult neurogenesis, and the GABAergic system in adult male and female Wistar rats. HAP1-ir cells, which were sporadically distributed particularly in the subgranular zone (SGZ) of the dentate gyrus and in the interface between the stratum lacunosum-moleculare and stratum radiatum of Ammon's horn, were identified as the "sporadically lurking HAP1-ir (SLH)" cells. The SLH cells showed no clear association with neural progenitor/proliferating or migrating cell markers of adult neurogenesis, such as Ki-67, proliferating cell nuclear antigen, doublecortin, and glial fibrillary acidic protein in the SGZ, whereas all the SLH cells expressed a neuronal specific nuclear protein (NeuN). More than 90% of the SLH cells expressed nuclear estrogen receptor (ER) α but neither ERβ nor the androgen receptor, whereas glucocorticoid receptor was differently stained in the SLH cells depending on the antibodies. More than 60% of them exhibited GABA immunoreactivity in the SGZ, suggestive of basket cells, but they were distinct from the ones expressing cholecystokinin or parvalbumin. We conclude that SLH cells, which should be stable against apoptosis due to putative HAP1 protectivity, might be involved in estrogen-dependent maturation, remodeling and activation of hippocampal memory and learning functions via ERα and partly through GABAergic regulation.
亨廷顿蛋白关联蛋白 1（HAP1）是一种神经亨廷顿相互作用蛋白，作为神经角质体（神经细胞质包含物）的核心分子广泛表达于边缘和下丘脑区域，具有针对某些神经退行性疾病的潜在保护作用（HAP1 保护假说）。尽管已经报道 HAP1 与几种类固醇受体密切相关，但在海马体中仍未鉴定出 HAP1-免疫反应（HAP1-ir）细胞，海马体是主要的类固醇靶标之一。在这项研究中，我们通过光和荧光显微镜确定了海马体 HAP1-ir 细胞的分布，并在成年雄性和雌性 Wistar 大鼠中对其形态与类固醇受体、成年神经发生标志物和 GABA 能系统的关系进行了特征描述。HAP1-ir 细胞散在分布，特别是在齿状回的颗粒下区（SGZ）和角回的腔隙状分子层和放射状层之间的界面处，被鉴定为“散在潜伏的 HAP1-ir（SLH）”细胞。SLH 细胞与成年神经发生的神经祖细胞/增殖或迁移细胞标志物（如 SGZ 中的 Ki-67、增殖细胞核抗原、双皮质素和神经胶质纤维酸性蛋白）没有明显关联，而所有 SLH 细胞均表达神经元特异性核蛋白（NeuN）。超过 90%的 SLH 细胞表达核雌激素受体（ER）α，但不表达 ERβ 或雄激素受体，而糖皮质激素受体在 SLH 细胞中的染色则因抗体而异。超过 60%的 SLH 细胞在 SGZ 中表现出 GABA 免疫反应，提示为篮状细胞，但它们与表达胆囊收缩素或副甲状腺素的细胞不同。我们得出结论，由于 HAP1 的潜在保护作用，SLH 细胞可能具有抗细胞凋亡的稳定性，它们可能通过 ERα 参与雌激素依赖性成熟、海马体记忆和学习功能的重塑和激活，并部分通过 GABA 能调节发挥作用。
