Department of Biomedicine/Physiology, University of Helsinki, PO Box 63, FIN-00014 Helsinki, Finland.
Neurobiol Dis. 2011 Feb;41(2):469-80. doi: 10.1016/j.nbd.2010.10.018. Epub 2010 Nov 1.
Fragile X syndrome (FXS) is a common cause of inherited mental retardation and the best characterized form of autistic spectrum disorders. FXS is caused by the loss of functional fragile X mental retardation protein (FMRP), which leads to abnormalities in the differentiation of neural progenitor cells (NPCs) and in the development of dendritic spines and neuronal circuits. Brain-derived neurotrophic factor (BDNF) and its TrkB receptors play a central role in neuronal maturation and plasticity. We studied BDNF/TrkB actions in the absence of FMRP and show that an increase in catalytic TrkB expression in undifferentiated NPCs of Fmr1-knockout (KO) mice, a mouse model for FXS, is associated with changes in the differentiation and migration of neurons expressing TrkB in neurosphere cultures and in the developing cortex. Aberrant intracellular calcium responses to BDNF and ATP in subpopulations of differentiating NPCs combined with changes in the expression of BDNF and TrkB suggest cell subtype-specific alterations during early neuronal maturation in the absence of FMRP. Furthermore, we show that dendritic targeting of Bdnf mRNA was increased under basal conditions and further enhanced in cortical layer V and hippocampal CA1 neurons of Fmr1-KO mice by pilocarpine-induced neuronal activity represented by convulsive seizures, suggesting that BDNF/TrkB-mediated feedback mechanisms for strengthening the synapses were compromised in the absence of FMRP. Pilocarpine-induced seizures caused an accumulation of Bdnf mRNA transcripts in the most proximal segments of dendrites in cortical but not in hippocampal neurons of Fmr1-KO mice. In addition, BDNF protein levels were increased in the hippocampus but reduced in the cortex of Fmr1-KO mice in line with regional differences of synaptic plasticity in the brain of Fmr1-KO mice. Altogether, the present data suggest that alterations in the BDNF/TrkB signaling modulate brain development and impair synaptic plasticity in FXS.
脆性 X 综合征（FXS）是一种常见的遗传性智力障碍，也是最具特征性的自闭症谱系障碍形式。FXS 是由于功能性脆性 X 智力低下蛋白（FMRP）的缺失引起的，这导致神经祖细胞（NPC）的分化和树突棘以及神经元回路的发育异常。脑源性神经营养因子（BDNF）及其 TrkB 受体在神经元成熟和可塑性中发挥核心作用。我们研究了缺乏 FMRP 时 BDNF/TrkB 的作用，并表明 Fmr1 敲除（KO）小鼠（FXS 的一种小鼠模型）未分化 NPC 中催化型 TrkB 表达的增加与神经球培养物中表达 TrkB 的神经元的分化和迁移以及发育中的皮质有关。在分化中的 NPC 的亚群中，BDNF 和 ATP 的异常细胞内钙反应与 BDNF 和 TrkB 表达的变化相结合，表明在缺乏 FMRP 的情况下，早期神经元成熟过程中存在细胞亚型特异性改变。此外，我们还表明，在基础条件下，Bdnf mRNA 的树突靶向增加，并且在 Fmr1-KO 小鼠的皮质第 V 层和海马 CA1 神经元中，由匹罗卡品诱导的神经元活动（表现为惊厥性发作）进一步增强，表明在缺乏 FMRP 的情况下，BDNF/TrkB 介导的增强突触的反馈机制受损。匹罗卡品诱导的惊厥导致 Bdnf mRNA 转录本在皮质而非海马 Fmr1-KO 小鼠神经元的树突最近端段积聚。此外，BDNF 蛋白水平在 Fmr1-KO 小鼠的海马体中增加，而在皮质中减少，与 Fmr1-KO 小鼠大脑中突触可塑性的区域差异一致。总的来说，这些数据表明 BDNF/TrkB 信号的改变调节了大脑发育并损害了 FXS 中的突触可塑性。
