Center for Neural Science, New York University, New York 10003, USA.
Synapse. 2012 Oct;66(10):870-9. doi: 10.1002/syn.21578. Epub 2012 Jul 20.
Presenilin conditional double knockout (PScDKO) mice have been used as animal models to study the development of Alzheimer's disease (AD) phenotypes. Studies to date indicate that these animals exhibit memory dysfunction and decreased synaptic plasticity before the onset of neurodegeneration. Therefore, the current study sought to examine how the loss of presenilin expression leads to these defects. Drebrin A, a neuron-specific actin-binding protein, has been shown to play an important role in the activity-dependent redistribution of the NMDA type of glutamate receptors at the synapse which, in turn, is a critical step for enabling synaptic plasticity. It is hypothesized that defects in the activity dependent redistribution of NMDA receptors in PScDKO mice may be due to loss of drebrin A. In this study, electron microscopic immunocytochemistry (EM-ICC) was used to quantify and locate drebrin A in the CA1 field of the hippocampus of PScDKO mice. The high resolution of EM-ICC allowed for differentiation between drebrin A at the synapse and at nonsynaptic sites, the latter of which would reflect the protein's role in regulating the reserve or degradative pool of NMDA receptors. The results here demonstrate that loss of function of presenilin in mice leads to a decrease in immunoreactivity for drebrin A at both synaptic (54% decrease, P < 0.01) and nonsynaptic areas (40% decrease, P < 0.01) and overall (44% decrease, P < 0.01). The reduction of drebrin A in both synaptic and nonsynaptic locations of the spine may implicate impairment in glutamate receptor trafficking to and from the postsynaptic plasma membrane. In addition, because of reduced drebrin A at nonsynaptic sites, the regulation of the reserve and degradative pools of glutamate receptors may also be impaired, leading to further synaptic dysfunction. Therefore, this study provides evidence to the theory that drebrin A has a causal role in compromising activity-dependent glutamate receptor trafficking in PScDKO mice.
早老素条件性双敲除（PScDKO）小鼠已被用作研究阿尔茨海默病（AD）表型发展的动物模型。迄今为止的研究表明，这些动物在神经退行性病变发生前表现出记忆功能障碍和突触可塑性降低。因此，本研究旨在探讨早老素表达缺失如何导致这些缺陷。脑桥蛋白 A（Drebrin A）是一种神经元特异性肌动蛋白结合蛋白，已被证明在突触中 NMDA 型谷氨酸受体的活性依赖性再分布中发挥重要作用，而 NMDA 型谷氨酸受体的活性依赖性再分布是突触可塑性的关键步骤。据推测，PScDKO 小鼠中 NMDA 受体的活性依赖性再分布缺陷可能是由于 drebrin A 的缺失。在这项研究中，电子显微镜免疫细胞化学（EM-ICC）用于定量和定位 PScDKO 小鼠海马 CA1 区的 drebrin A。EM-ICC 的高分辨率允许区分突触和非突触部位的 drebrin A，后者反映了该蛋白在调节 NMDA 受体的储备或降解池中的作用。研究结果表明，在小鼠中早老素功能丧失导致突触（减少 54%，P < 0.01）和非突触区域（减少 40%，P < 0.01）以及总体（减少 44%，P < 0.01）处 drebrin A 的免疫反应性降低。突触棘突的突触和非突触部位 drebrin A 的减少可能暗示谷氨酸受体向和从突触后质膜的转运受损。此外，由于非突触部位的 drebrin A 减少，谷氨酸受体的储备和降解池的调节也可能受损，导致进一步的突触功能障碍。因此，本研究为 drebrin A 在 PScDKO 小鼠中导致活性依赖性谷氨酸受体转运受损的理论提供了证据。
