Fragile X Mental Retardation Protein and Dendritic Local Translation of the Alpha Subunit of the Calcium/Calmodulin-Dependent Kinase II Messenger RNA Are Required for the Structural Plasticity Underlying Olfactory Learning

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• 作者：Laura Daroles^a ; Simona Gribaudo^a ; Mohamed Doulazmi^a ; Sophie Scotto-Lomassese^a ; Caroline Dubacq^a ; Nathalie Mandairon^c ; Charles August Greer^d ; Anne Didier^c ; Alain Trembleau^a ; Isabelle Caillé ; ^a ; ^b ; ^{isabelle.caille@snv.jussieu.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Adult neurogenesis ; Fragile X mental retardation protein ; Learning ; Local translation ; Olfactory bulb ; Structural plasticity
• 刊名：Biological Psychiatry
• 出版年：2016
• 出版时间：15 July 2016
• 年：2016
• 卷：80
• 期：2
• 页码：149-159
• 全文大小：1908 K

文摘

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.

Methods

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.

Results

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.

Conclusions

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.