Starling Amaal J, André Véronique M, Cepeda Carlos, de Lima Marianne, Chandler Scott H, Levine Michael S
Mental Retardation Research Center, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA.
J Neurosci Res. 2005 Nov 1;82(3):377-86. doi: 10.1002/jnr.20651.
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder that affects primarily the striatum and cerebral cortex. A search for the factors that increase the vulnerability of striatal neurons will lead to a better understanding of the pathological cascades of this disease. A current hypothesis for neurodegeneration of striatal medium-sized spiny neurons in HD is an alteration in N-methyl-D-aspartate (NMDA) receptor function. In the present study we examined electrophysiological properties of NMDA receptors in the R6/2 transgenic mouse model. These animals express exon 1 of the human HD gene and present an overt behavioral phenotype at about 5 weeks of age. Whole-cell voltage clamp recordings from acutely dissociated striatal neurons were obtained from three different age groups of transgenic mice (15, 21, and 40 days old) and their littermate controls (WT). In transgenic animals, two groups of neurons were found with respect to NMDA and Mg2+ sensitivity. One group of R6/2 cells displayed responses similar to those of WT, whereas the other showed increased responses to NMDA and decreased Mg2+ sensitivity. These cells were encountered in all age groups. The abnormal sensitivity to NMDA and Mg2+ indicates that NMDA receptor alterations occur very early in development and suggest the presence of constitutively abnormal NMDA receptors. These alterations may contribute to an enhancement of NMDA responses at hyperpolarized membrane potentials that may be a key factor in striatal neuronal dysfunction.
亨廷顿舞蹈症（HD）是一种常染色体显性神经退行性疾病，主要影响纹状体和大脑皮层。寻找增加纹状体神经元易损性的因素将有助于更好地理解该疾病的病理过程。目前关于HD中纹状体中等大小棘状神经元神经退行性变的假说是N-甲基-D-天冬氨酸（NMDA）受体功能发生改变。在本研究中，我们检测了R6/2转基因小鼠模型中NMDA受体的电生理特性。这些动物表达人类HD基因的外显子1，并在约5周龄时呈现明显的行为表型。从急性分离的纹状体神经元进行全细胞膜片钳记录，记录来自三个不同年龄组的转基因小鼠（15、21和40日龄）及其同窝对照（野生型）。在转基因动物中，发现两组神经元在NMDA和Mg2+敏感性方面存在差异。一组R6/2细胞的反应与野生型相似，而另一组对NMDA的反应增强，对Mg2+的敏感性降低。所有年龄组均出现这些细胞。对NMDA和Mg2+的异常敏感性表明NMDA受体改变在发育早期就已发生，并提示存在组成性异常的NMDA受体。这些改变可能导致在超极化膜电位下NMDA反应增强，这可能是纹状体神经元功能障碍的关键因素。
