Abnormal Development of Dendritic Spines inFMR1Knock-Out Mice

作者：Esther A. Nimchinsky, Adam M. Oberlander, Karel Svoboda · 发表于：Journal of Neuroscience · 年份：2001 · DOI：10.1523/jneurosci.21-14-05139.2001 · 被引用次数：472 · 研究领域：Genetics and Neurodevelopmental Disorders、Autism Spectrum Disorder Research、Ubiquitin and proteasome pathways

Fragile X syndrome is caused by a mutation in theFMR1gene leading to absence of the fragile X mental retardation protein (FMRP). Reports that patients and adultFMR1knock-out mice have abnormally long dendritic spines of increased density suggested that the disorder might involve abnormal spine development. Because spine length, density, and motility change dramatically in the first postnatal weeks, we analyzed these properties in mutant mice and littermate controls at 1, 2, and 4 weeks of age. To label neurons, a viral vector carrying the enhanced green fluorescent protein gene was injected into the barrel cortex. Layer V neurons were imaged on a two-photon laser scanning microscope in fixed tissue sections. Analysis of >16,000 spines showed clear developmental patterns. Between 1 and 4 weeks of age, spine density increased 2.5-fold, and mean spine length decreased by 17% in normal animals. Early during cortical synaptogenesis, pyramidal cells in mutant mice had longer spines than controls. At 1 week, spine length was 28% greater in mutants than in controls. At 2 weeks, this difference was 10%, and at 4 weeks only 3%. Similarly, spine density was 33% greater in mutants than in controls at 1 week of age. At 2 or 4 weeks of age, differences were not detectable. The spine abnormality was not detected in neocortical organotypic cultures. The transient nature of the spine abnormality in the intact animal suggests that FMRP might play a role in the normal process of dendritic spine...