Kogan Cary S, Boutet Isabelle, Cornish Kim, Zangenehpour Shahin, Mullen Kathy T, Holden Jeanette J A, Der Kaloustian Vazken M, Andermann Eva, Chaudhuri Avi
Department of Psychology, McGill University, Montréal, Québec, Canada.
Brain. 2004 Mar;127(Pt 3):591-601. doi: 10.1093/brain/awh069. Epub 2004 Jan 21.
Fragile X syndrome (FXS) is the most common form of heritable mental retardation, affecting approximately 1 in 4000 males. The syndrome arises from expansion of a trinucleotide repeat in the 5'-untranslated region of the fragile X mental retardation 1 (FMR1) gene, leading to methylation of the promoter sequence and lack of the fragile X mental retardation protein (FMRP). Affected individuals display a unique neurobehavioural phenotype that includes striking visual-motor deficits. Here we provide neurobiological and behavioural evidence that supports the hypothesis that these visual-motor deficits are attributable to a magnocellular (M) visual pathway impairment. Immunohistochemical staining of a lateral geniculate nucleus (LGN) of a normal human male revealed high FMRP basal expression selectively within the M layers, suggesting an increased susceptibility of these neurons to the lack of FMRP as occurs in FXS. Similar staining of monkey LGNs for quantification purposes revealed that the difference is not an artefact of cell size differences between M and parvocellular (P) neurons. Further, Nissl staining of the LGNs of a male FXS patient revealed alaminar nuclei comprised of a homogenous population of small sized neurons, providing anatomical and morphological support for the idea that an M pathway pathology exists in FXS. Consistent with these neurobiological data, we have found that male patients with FXS have reduced sensitivity for psychophysical stimuli that probe the M pathway but not for those that probe the P pathway, a complementary visual stream that performs a separate set of early visual operations. Finally, male patients with FXS performed poorly on a global motion task but not on a form perception task, suggesting that the M pathway thalamic deficit may have a selective impact on cortical visual functioning in the parietal lobe, which is known to be a major recipient of M pathway afferents via the primary visual cortex. Together, these findings provide the first evidence that the loss of a single gene product, FMRP, in humans leads to abnormal neuroanatomical morphology of the LGN and a concomitant selective visual deficit of the M pathway.
脆性X综合征（FXS）是遗传性智力障碍最常见的形式，约每4000名男性中就有1人受其影响。该综合征源于脆性X智力障碍1（FMR1）基因5'非翻译区三核苷酸重复序列的扩增，导致启动子序列甲基化以及脆性X智力障碍蛋白（FMRP）缺失。受影响个体表现出独特的神经行为表型，包括明显的视觉运动缺陷。在此，我们提供神经生物学和行为学证据，支持这些视觉运动缺陷归因于大细胞（M）视觉通路损伤这一假说。对一名正常男性人类外侧膝状体（LGN）进行免疫组织化学染色显示，FMRP基础表达在M层中选择性地高表达，这表明这些神经元对FXS中出现的FMRP缺失更敏感。为了进行量化，对猴LGN进行类似染色显示，这种差异并非M神经元和小细胞（P）神经元之间细胞大小差异造成的假象。此外，对一名男性FXS患者的LGN进行尼氏染色显示，板层核由均匀的小尺寸神经元群体组成，为FXS中存在M通路病理这一观点提供了解剖学和形态学支持。与这些神经生物学数据一致，我们发现FXS男性患者对探测M通路的心理物理学刺激的敏感性降低，但对探测P通路（执行另一组早期视觉操作的互补视觉流）的刺激不敏感。最后，FXS男性患者在全局运动任务中表现不佳，但在形状感知任务中表现正常，这表明M通路丘脑缺陷可能对顶叶皮质视觉功能有选择性影响，已知顶叶是通过初级视觉皮质接收M通路传入纤维的主要区域。总之，这些发现首次证明，人类中单一基因产物FMRP的缺失会导致LGN神经解剖形态异常以及M通路相应的选择性视觉缺陷。
