Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France.
Université Lyon1, CNRS UMR 5292, INSERM U1028, Centre de Recherche en Neurosciences de Lyon.
Biol Psychiatry. 2016 Jul 15;80(2):149-159. doi: 10.1016/j.biopsych.2015.07.023. Epub 2015 Aug 7.
In the adult brain, structural plasticity allowing gain or loss of synapses remodels circuits to support learning. In fragile X syndrome, the absence of fragile X mental retardation protein (FMRP) leads to defects in plasticity and learning deficits. FMRP is a master regulator of local translation but its implication in learning-induced structural plasticity is unknown.
Using an olfactory learning task requiring adult-born olfactory bulb neurons and cell-specific ablation of FMRP, we investigated whether learning shapes adult-born neuron morphology during their synaptic integration and its dependence on FMRP. We used alpha subunit of the calcium/calmodulin-dependent kinase II (αCaMKII) mutant mice with altered dendritic localization of αCaMKII messenger RNA, as well as a reporter of αCaMKII local translation to investigate the role of this FMRP messenger RNA target in learning-dependent structural plasticity.
Learning induces profound changes in dendritic architecture and spine morphology of adult-born neurons that are prevented by ablation of FMRP in adult-born neurons and rescued by an metabotropic glutamate receptor 5 antagonist. Moreover, dendritically translated αCaMKII is necessary for learning and associated structural modifications and learning triggers an FMRP-dependent increase of αCaMKII dendritic translation in adult-born neurons.
Our results strongly suggest that FMRP mediates structural plasticity of olfactory bulb adult-born neurons to support olfactory learning through αCaMKII local translation. This reveals a new role for FMRP-regulated dendritic local translation in learning-induced structural plasticity. This might be of clinical relevance for the understanding of critical periods disruption in autism spectrum disorder patients, among which fragile X syndrome is the primary monogenic cause.
在成人的大脑中，允许突触增减的结构可塑性重塑了电路，以支持学习。在脆性 X 综合征中，由于缺乏脆性 X 智力迟钝蛋白（FMRP），导致可塑性缺陷和学习缺陷。FMRP 是局部翻译的主要调节因子，但它在学习诱导的结构可塑性中的作用尚不清楚。
使用需要成年产生的嗅球神经元和细胞特异性 FMRP 消融的嗅觉学习任务，我们研究了学习是否在其突触整合期间塑造成年产生的神经元形态，以及其对 FMRP 的依赖性。我们使用钙/钙调蛋白依赖性激酶 II（αCaMKII）的 α 亚单位突变小鼠，其 αCaMKII 信使 RNA 的树突定位发生改变，以及 αCaMKII 局部翻译的报告基因，以研究该 FMRP 信使 RNA 靶标在学习依赖性结构可塑性中的作用。
学习诱导成年产生的神经元的树突结构和棘突形态发生深刻变化，而在成年产生的神经元中消融 FMRP 可阻止这种变化，并通过代谢型谷氨酸受体 5 拮抗剂挽救。此外，树突翻译的 αCaMKII 对于学习和相关的结构修饰是必需的，并且学习触发了 FMRP 依赖性的成年产生的神经元中 αCaMKII 树突翻译的增加。
我们的结果强烈表明，FMRP 通过 αCaMKII 局部翻译介导嗅球成年产生的神经元的结构可塑性，以支持嗅觉学习。这揭示了 FMRP 调节的树突局部翻译在学习诱导的结构可塑性中的新作用。这对于理解自闭症谱系障碍患者的关键期破坏可能具有临床意义，其中脆性 X 综合征是主要的单基因原因。
