Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, United States.
Departments of Neurology and Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, United States.
Elife. 2017 Sep 11;6:e29178. doi: 10.7554/eLife.29178.
Neuronal ApoE receptors are linked to learning and memory, but the pathways governing their abundance, and the mechanisms by which they affect the function of neural circuits are incompletely understood. Here we demonstrate that the E3 ubiquitin ligase IDOL determines synaptic ApoER2 protein levels in response to neuronal activation and regulates dendritic spine morphogenesis and plasticity. IDOL-dependent changes in ApoER2 abundance modulate dendritic filopodia initiation and synapse maturation. Loss of IDOL in neurons results in constitutive overexpression of ApoER2 and is associated with impaired activity-dependent structural remodeling of spines and defective LTP in primary neuron cultures and hippocampal slices. IDOL-deficient mice show profound impairment in experience-dependent reorganization of synaptic circuits in the barrel cortex, as well as diminished spatial and associative learning. These results identify control of lipoprotein receptor abundance by IDOL as a post-transcriptional mechanism underlying the structural and functional plasticity of synapses and neural circuits.
神经元 ApoE 受体与学习和记忆有关，但调节其丰度的途径以及它们影响神经回路功能的机制尚不完全清楚。在这里，我们证明 E3 泛素连接酶 IDOL 可响应神经元激活来确定突触 ApoER2 蛋白水平，并调节树突棘形态发生和可塑性。IDOL 依赖性的 ApoER2 丰度变化调节树突丝状伪足的起始和突触成熟。神经元中 IDOL 的缺失导致 ApoER2 的组成性过表达，并伴有与活动依赖性棘突结构重塑受损和原代神经元培养物和海马切片中长时程增强作用缺陷相关的缺陷。IDOL 缺陷型小鼠在桶状皮层中表现出突触回路的经验依赖性重组严重受损，以及空间和联想学习能力下降。这些结果表明，IDOL 通过控制脂蛋白受体的丰度作为突触和神经回路结构和功能可塑性的转录后机制。
