Department of Physiology, Anatomy and Cell Biology, University Pablo de Olavide, Ctra Utrera km. 1, 41013, Seville, Spain.
División de Ciencias de la Salud e Ingenierías, Universidad de Guanajuato, Campus Celaya-Salvatierra, Guanajuato, Mexico.
Mol Neurobiol. 2018 Feb;55(2):1157-1168. doi: 10.1007/s12035-016-0371-8. Epub 2017 Jan 19.
Tambaleante (tbl/tbl) is a mutant mouse that carries a spontaneous Gly483Glu substitution in the HERC1 (HECT domain and RCC1 domain) E3 ubiquitin ligase protein (HERC1). The tbl/tbl mutant suffers an ataxic syndrome given the almost complete loss of cerebellar Purkinje cells during adult life. More recent analyses have identified alterations at neuromuscular junctions in these mice, as well as in other neurons of the central nervous system, such as motor neurons in the spinal cord, or pyramidal neurons in the hippocampal CA3 region and the neocortex. Accordingly, the effect of the tbl/tbl mutation apparently extends to other regions of the nervous system far from the cerebellum. As HERC1 mutations in humans have been correlated with intellectual impairment, we studied the effect of the tbl/tbl mutation on learning. Using a behavioral test, ex vivo electrophysiological recordings, immunohistochemistry, and Golgi method, we analyzed the associative learning in the lateral amygdala of the tbl/tbl mouse. The tbl/tbl mice perform worse than wild-type animals in the passive avoidance test, and histologically, the tbl/tbl mice have more immature forms of dendritic spines. In addition, LTP cannot be detected in these animals and their STP is dampened, as is their glutamatergic input to the lateral amygdala. Together, these data suggest that HERC1 is probably involved in regulating synaptic function in the amygdala. Indeed, these results indicate that the tbl/tbl mutation is a good model to analyze the effect of alterations to the ubiquitin-proteasome pathway on the synaptic mechanisms involved in learning and its defects.
摇摆（tbl/tbl）是一种突变鼠，其携带 HERC1（HECT 结构域和 RCC1 结构域）E3 泛素连接酶蛋白中的自发 Gly483Glu 取代。tbl/tbl 突变体在成年期几乎完全丧失小脑浦肯野细胞时会出现共济失调综合征。最近的分析还发现这些小鼠的神经肌肉接头以及中枢神经系统的其他神经元（例如脊髓中的运动神经元或海马 CA3 区和新皮层中的锥体神经元）发生了改变。因此，tbl/tbl 突变的影响显然扩展到远离小脑的神经系统的其他区域。由于人类的 HERC1 突变与智力障碍有关，因此我们研究了 tbl/tbl 突变对学习的影响。使用行为测试，离体电生理记录，免疫组织化学和高尔基方法，我们分析了 tbl/tbl 小鼠外侧杏仁核的联想学习。tbl/tbl 小鼠在被动回避测试中的表现不如野生型动物，组织学上，tbl/tbl 小鼠具有更多不成熟的树突棘形式。此外，这些动物中不能检测到 LTP，其 STP 减弱，其谷氨酸能输入到外侧杏仁核也减弱。这些数据表明，HERC1 可能参与调节杏仁核中的突触功能。实际上，这些结果表明，tbl/tbl 突变是分析泛素-蛋白酶体途径改变对学习及其缺陷所涉及的突触机制的影响的良好模型。
