Department of Developmental Neuroscience, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, Nebraska 68198-5960.
J Neurosci. 2013 Dec 11;33(50):19715-23. doi: 10.1523/JNEUROSCI.2514-13.2013.
Fragile X syndrome (FXS) is the most common inherited intellectual disability. FXS results from a mutation that causes silencing of the FMR1 gene, which encodes the fragile X mental retardation protein. Patients with FXS exhibit a range of neurological deficits, including motor skill deficits. Here, we have investigated motor skill learning and its synaptic correlates in the fmr1 knock-out (KO) mouse. We find that fmr1 KO mice have impaired motor skill learning of a forelimb-reaching task, compared with their wild-type (WT) littermate controls. Electrophysiological recordings from the forelimb region of the primary motor cortex demonstrated reduced, training-induced synaptic strengthening in the trained hemisphere. Moreover, long-term potentiation (LTP) is impaired in the fmr1 KO mouse, and motor skill training does not occlude LTP as it does in the WT mice. Whereas motor skill training induces an increase of synaptic AMPA-type glutamate receptor subunit 1 (GluA1), there is a delay in GluA1 increase in the trained hemisphere of the fmr1 KO mice. Using transcranial in vivo multiphoton microscopy, we find that fmr1 KO mice have similar spine density but increased dendritic spine turnover compared with WT mice. Finally, we report that motor skill training-induced formation of dendritic spines is impaired in fmr1 KO mice. We conclude that FMRP plays a role in motor skill learning and that reduced functional and structural synaptic plasticity might underlie the behavioral deficit in the fmr1 KO mouse.
脆性 X 综合征（FXS）是最常见的遗传性智力障碍。FXS 是由于突变导致 FMR1 基因沉默引起的，该基因编码脆性 X 智力低下蛋白。FXS 患者表现出一系列神经功能缺陷，包括运动技能缺陷。在这里，我们研究了 fmr1 敲除（KO）小鼠的运动技能学习及其突触相关性。我们发现，与野生型（WT）同窝对照相比，fmr1 KO 小鼠在前肢伸展任务的运动技能学习中受损。来自初级运动皮层前肢区域的电生理记录显示，在训练半球中，训练诱导的突触强化减少。此外，fmr1 KO 小鼠中的长时程增强（LTP）受损，而运动技能训练不会像 WT 小鼠那样阻断 LTP。虽然运动技能训练会导致突触 AMPA 型谷氨酸受体亚基 1（GluA1）增加，但在 fmr1 KO 小鼠的训练半球中，GluA1 的增加会延迟。使用颅外体内多光子显微镜，我们发现 fmr1 KO 小鼠的棘突密度相似，但与 WT 小鼠相比，棘突转换率增加。最后，我们报告说，fmr1 KO 小鼠的运动技能训练诱导的树突棘形成受损。我们得出结论，FMRP 在运动技能学习中发挥作用，而功能和结构突触可塑性降低可能是 fmr1 KO 小鼠行为缺陷的基础。
