Desai Niraj S, Casimiro Tanya M, Gruber Stephen M, Vanderklish Peter W
The Neurosciences Fine Institute, San Diego, CA 92121, USA.
J Neurophysiol. 2006 Oct;96(4):1734-45. doi: 10.1152/jn.00221.2006. Epub 2006 Jul 5.
Fragile X syndrome is produced by a defect in a single X-linked gene, called Fmr1, and is characterized by abnormal dendritic spine morphologies with spines that are longer and thinner in neocortex than those from age-matched controls. Studies using Fmr1 knockout mice indicate that spine abnormalities are especially pronounced in the first month of life, suggesting that altered developmental plasticity underlies some of the behavioral phenotypes associated with the syndrome. To address this issue, we used intracellular recordings in neocortical slices from early postnatal mice to examine the effects of Fmr1 disruption on two forms of plasticity active during development. One of these, long-term potentiation of intrinsic excitability, is intrinsic in expression and requires mGluR5 activation. The other, spike timing-dependent plasticity, is synaptic in expression and requires N-methyl-d-aspartate receptor activation. While intrinsic plasticity was normal in the knockout mice, synaptic plasticity was altered in an unusual and striking way: long-term depression was robust but long-term potentiation was entirely absent. These findings underscore the ideas that Fmr1 has highly selective effects on plasticity and that abnormal postnatal development is an important component of the disorder.
脆性X综合征由一个名为Fmr1的单基因X连锁缺陷引起，其特征是树突棘形态异常，新皮层中的树突棘比年龄匹配的对照更长更细。使用Fmr1基因敲除小鼠的研究表明，树突棘异常在出生后的第一个月尤为明显，这表明发育可塑性的改变是该综合征相关行为表型的基础。为了解决这个问题，我们使用产后早期小鼠新皮层切片的细胞内记录来研究Fmr1缺失对发育过程中两种可塑性形式的影响。其中一种，内在兴奋性的长期增强，在表达上是内在的，需要mGluR5激活。另一种，峰电位时间依赖可塑性，在表达上是突触性的，需要N-甲基-D-天冬氨酸受体激活。虽然基因敲除小鼠的内在可塑性正常，但突触可塑性却以一种不同寻常且惊人的方式发生了改变：长期抑制很强，但长期增强完全不存在。这些发现强调了Fmr1对可塑性具有高度选择性影响的观点，以及出生后发育异常是该疾病的一个重要组成部分。
