Interdisciplinary Program in Biomedical Sciences, College of Medicine, University of Florida, Gainesville, Florida, United States of America.
PLoS One. 2012;7(4):e35518. doi: 10.1371/journal.pone.0035518. Epub 2012 Apr 19.
Polymorphisms in BTBD9 have recently been associated with higher risk of restless legs syndrome (RLS), a neurological disorder characterized by uncomfortable sensations in the legs at rest that are relieved by movement. The BTBD9 protein contains a BTB/POZ domain and a BACK domain, but its function is unknown. To elucidate its function and potential role in the pathophysiology of RLS, we generated a line of mutant Btbd9 mice derived from a commercial gene-trap embryonic stem cell clone. Btbd9 is the mouse homolog of the human BTBD9. Proteins that contain a BTB/POZ domain have been reported to be associated with synaptic transmission and plasticity. We found that Btbd9 is naturally expressed in the hippocampus of our mutant mice, a region critical for learning and memory. As electrophysiological characteristics of CA3-CA1 synapses of the hippocampus are well characterized, we performed electrophysiological recordings in this region. The mutant mice showed normal input-output relationship, a significant impairment in pre-synaptic activity, and an enhanced long-term potentiation. We further performed an analysis of fear memory and found the mutant mice had an enhanced cued and contextual fear memory. To elucidate a possible molecular basis for these enhancements, we analyzed proteins that have been associated with synaptic plasticity. We found an elevated level of dynamin 1, an enzyme associated with endocytosis, in the mutant mice. These results suggest the first identified function of Btbd9 as being involved in regulating synaptic plasticity and memory. Recent studies have suggested that enhanced synaptic plasticity, analogous to what we have observed, in other regions of the brain could enhance sensory perception similar to what is seen in RLS patients. Further analyses of the mutant mice will help shine light on the function of BTBD9 and its role in RLS.
BTBD9 基因的多态性最近与不宁腿综合征（RLS）的高风险相关，RLS 是一种以腿部休息时不适的感觉为特征的神经系统疾病，运动可以缓解这种不适。BTBD9 蛋白包含一个 BTB/POZ 结构域和一个 BACK 结构域，但它的功能未知。为了阐明其功能及其在 RLS 病理生理学中的潜在作用，我们从商业基因捕获胚胎干细胞克隆中生成了一条突变 Btbd9 小鼠系。Btbd9 是人类 BTBD9 的小鼠同源物。含有 BTB/POZ 结构域的蛋白质已被报道与突触传递和可塑性有关。我们发现 Btbd9 在我们突变小鼠的海马体中自然表达，海马体是学习和记忆的关键区域。由于海马体 CA3-CA1 突触的电生理特征得到了很好的描述，我们在该区域进行了电生理记录。突变小鼠表现出正常的输入-输出关系，前突触活动显著受损，长时程增强增强。我们进一步进行了恐惧记忆分析，发现突变小鼠的提示性和情境性恐惧记忆增强。为了阐明这些增强的可能分子基础，我们分析了与突触可塑性相关的蛋白质。我们发现突变小鼠中的动力蛋白 1（一种与内吞作用相关的酶）水平升高。这些结果表明 Btbd9 的第一个确定功能是参与调节突触可塑性和记忆。最近的研究表明，大脑其他区域增强的突触可塑性，类似于我们观察到的，可能增强类似 RLS 患者所见的感觉感知。对突变小鼠的进一步分析将有助于阐明 BTBD9 的功能及其在 RLS 中的作用。
