Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD, 21205, United States; Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, 23298, United States; Eunice Kennedy Shriver, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, United States.
Department of Gynecology and Obstetrics, Johns Hopkins School of Medicine, Baltimore, MD, 21205, United States.
Brain Res Bull. 2018 Jun;140:72-79. doi: 10.1016/j.brainresbull.2018.04.005. Epub 2018 Apr 10.
Hormonal contributions to the sex-dependent development of both obsessive-compulsive disorder (OCD) and obesity have been described, but the underlying mechanisms are incompletely understood. A-kinase anchoring protein 13 (AKAP13) significantly augments ligand-dependent activation of estrogen receptors alpha and beta. The hypothalamus and pituitary gland are implicated in the development and exacerbation of OCD and obesity and have strong AKAP13 expression. The AKAP13 localization pattern observed in these key brain regions together with its effects on sex steroid action suggest a potential role for AKAP13 in compulsive-like behaviors. Here we tested the role of AKAP13 in compulsive-like behavior and body weight using an Akap13 haploinsufficient murine model.
Targeted deletion of the Akap13 gene generated haploinsufficient (Akap13+/-) mice in a C57BL6/J genetic background. Established behavioral assays were conducted, video recorded, and scored blindly to assess compulsive-like behavior based on genotype and gender. Tests included: marble-burying, grooming, open- field and elevated plus-maze. Brain and body weights were also obtained. Mean levels of test outcomes were compared using multi-way ANOVA to test for genotype, sex, genotypesex, and genotypesex*age interaction effects with Bonferroni adjustment for multiple comparisons, to further explain any significant interactions.
The marble-burying and grooming assays revealed significant sex-dependent increases in perseverative, compulsive-like behaviors in female Akap13 haploinsufficient mice compared to female wild type (WT) mice by demonstrating increased marble-burying activity (p = .0025) and a trend towards increased grooming behavior (p = .06). Male Akap13 haploinsufficient mice exhibited no behavioral changes (p > 0.05). Elevated plus-maze and open-field test results showed no overt anxiety-like behavior in Akap13 haploinsufficient mice irrespective of sex (p > 0.05, both). No differences in brain weight were found in Akap13 haploinsufficient mice compared to WT mice (p > 0.05). However, female Akap13 haploinsufficient mice weighed more than female WT mice in the 4 to <7 months age range (p = .0051). Male Akap13 haploinsufficient mice showed no differences in weight compared to male WT mice (p = >0.05) at any age range examined.
Akap13 haploinsufficiency led to sex-dependent, compulsive-like behavioral changes in a murine model. Interestingly, Akap13 haploinsufficiency also led to a sex-dependent increase in body weight. These results revealed a requirement for AKAP13 in murine behavior, particularly in female mice, and is the first report of AKAP13 involvement in murine behavior. Future studies may examine the involvement of AKAP13 in the pathophysiology of OCD in female humans and may contribute to a better understanding of the role of AKAP13 and sex hormones in the development and exacerbation of OCD.
已经描述了激素对强迫症（OCD）和肥胖的性别依赖性发展的贡献，但潜在的机制仍不完全清楚。A-激酶锚定蛋白 13（AKAP13）显著增强了雌激素受体α和β配体依赖性激活。下丘脑和垂体参与了 OCD 和肥胖的发展和恶化，并且具有强烈的 AKAP13 表达。在这些关键脑区观察到的 AKAP13 定位模式及其对性激素作用的影响表明 AKAP13 在强迫样行为中可能发挥作用。在这里，我们使用 Akap13 杂合不足的小鼠模型测试了 AKAP13 在强迫样行为和体重中的作用。
靶向敲除 Akap13 基因在 C57BL6/J 遗传背景下产生杂合不足（Akap13+/-）小鼠。进行了既定的行为测试，进行了视频记录，并根据基因型和性别进行了盲评分，以评估强迫样行为。测试包括：大理石掩埋、梳理、旷场和高架十字迷宫。还获得了大脑和体重。使用多因素方差分析比较平均测试结果，以测试基因型、性别、基因型性别、基因型性别*年龄相互作用的影响，并进行 Bonferroni 调整以进行多次比较，以进一步解释任何显著的相互作用。
大理石掩埋和梳理试验显示，与野生型（WT）雌性小鼠相比，雌性 Akap13 杂合不足小鼠表现出显著的性别依赖性强迫样行为增加，表现为大理石掩埋活性增加（p=0.0025）和梳理行为呈趋势增加（p=0.06）。雄性 Akap13 杂合不足小鼠没有表现出行为变化（p>0.05）。高架十字迷宫和旷场测试结果显示，Akap13 杂合不足小鼠无论性别均无明显的焦虑样行为（p>0.05，均）。Akap13 杂合不足小鼠的脑重与 WT 小鼠无差异（p>0.05）。然而，4 至<7 个月龄的雌性 Akap13 杂合不足小鼠的体重大于雌性 WT 小鼠（p=0.0051）。在任何检查的年龄范围内，雄性 Akap13 杂合不足小鼠的体重与雄性 WT 小鼠无差异（p>0.05）。
Akap13 杂合不足导致了小鼠模型中的性别依赖性强迫样行为改变。有趣的是，Akap13 杂合不足也导致了雌性体重的性别依赖性增加。这些结果揭示了 AKAP13 在小鼠行为中的必要性，特别是在雌性小鼠中，并且是 AKAP13 参与小鼠行为的首次报道。未来的研究可能会研究 AKAP13 在女性 OCD 病理生理学中的作用，并有助于更好地理解 AKAP13 和性激素在 OCD 的发展和恶化中的作用。
