Van Damme P, Van Den Bosch L, Van Houtte E, Callewaert G, Robberecht W
Laboratory for Neurobiology, University of Leuven, B-3000 Leuven, Belgium.
J Neurophysiol. 2002 Sep;88(3):1279-87. doi: 10.1152/jn.2002.88.3.1279.
AMPA receptor-mediated excitotoxicity has been implicated in the selective motor neuron loss in amyotrophic lateral sclerosis. In some culture models, motor neurons have been shown to be selectively vulnerable to AMPA receptor agonists due to Ca(2+) influx through Ca(2+)-permeable AMPA receptors. Because the absence of GluR2 in AMPA receptors renders them highly permeable to Ca(2+) ions, it has been hypothesized that the selective vulnerability of motor neurons is due to their relative deficiency in GluR2. However, conflicting evidence exists about the in vitro and in vivo expression of GluR2 in motor neurons, both at the mRNA and at the protein level. In this study, we quantified electrophysiological properties of AMPA receptors, known to be dependent on the relative abundance of GluR2: sensitivity to external polyamines, rectification index, and relative Ca(2+) permeability. Cultured rat spinal cord motor neurons were compared with dorsal horn neurons (which are resistant to excitotoxicity) and with motor neurons that survived an excitotoxic insult. Motor neurons had a higher sensitivity to external polyamines, a lower rectification index, and a higher relative Ca(2+) permeability ratio than dorsal horn neurons. These findings confirm that motor neurons are relatively deficient in GluR2. The AMPA receptor properties correlated well with each other and with the selective vulnerability of motor neurons because motor neurons surviving an excitotoxic event had similar characteristics as dorsal horn neurons. These data indicate that the relative abundance of GluR2 in functional AMPA receptors may be a major determinant of the selective vulnerability of motor neurons to excitotoxicity in vitro.
AMPA 受体介导的兴奋毒性与肌萎缩侧索硬化症中运动神经元的选择性丧失有关。在一些培养模型中，运动神经元已被证明由于 Ca(2+) 通过 Ca(2+) 通透型 AMPA 受体流入而对 AMPA 受体激动剂具有选择性易损性。由于 AMPA 受体中缺乏 GluR2 使其对 Ca(2+) 离子具有高度通透性，因此有人推测运动神经元的选择性易损性是由于它们相对缺乏 GluR2。然而，关于运动神经元中 GluR2 在体外和体内 mRNA 及蛋白质水平的表达存在相互矛盾的证据。在本研究中，我们量化了已知依赖于 GluR2 相对丰度的 AMPA 受体的电生理特性：对外部多胺的敏感性、整流指数和相对 Ca(2+) 通透性。将培养的大鼠脊髓运动神经元与背角神经元（对兴奋毒性有抗性）以及在兴奋毒性损伤后存活的运动神经元进行比较。运动神经元比背角神经元对外部多胺具有更高的敏感性、更低的整流指数和更高的相对 Ca(2+) 通透率。这些发现证实运动神经元相对缺乏 GluR2。AMPA 受体特性彼此之间以及与运动神经元的选择性易损性密切相关，因为在兴奋毒性事件后存活的运动神经元具有与背角神经元相似的特征。这些数据表明，功能性 AMPA 受体中 GluR2 的相对丰度可能是体外运动神经元对兴奋毒性选择性易损性的主要决定因素。
