title: 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.
abstract: 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.
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France.
authors.forename: Laura
authors.initials: L
authors.lastname: Daroles
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France.
authors.forename: Simona
authors.initials: S
authors.lastname: Gribaudo
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Doulazmi
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Scotto-Lomassese
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Dubacq
authors.affiliation: Université Lyon1, CNRS UMR 5292, INSERM U1028, Centre de Recherche en Neurosciences de Lyon.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Mandairon
authors.affiliation: Yale University School of Medicine, Department of Neurosurgery, New Haven, Connecticut.
authors.forename: Charles August
authors.initials: CA
authors.lastname: Greer
authors.affiliation: Université Lyon1, CNRS UMR 5292, INSERM U1028, Centre de Recherche en Neurosciences de Lyon.
authors.forename: Anne
authors.initials: A
authors.lastname: Didier
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Trembleau
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France; Sorbonne Paris Cité, Université Paris Diderot-Paris 7. Electronic address: isabelle.caille@snv.jussieu.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Caillé
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003712:Dendrites / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism; D007858:Learning / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology*; D055696:Olfactory Perception / Q000502:physiology*; D012333:RNA, Messenger
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051860:Fragile X Messenger Ribonucleoprotein 1; D012333:RNA, Messenger; C497684:Fmr1 protein, mouse; C517671:Camk2a protein, mouse
keywords: Adult neurogenesis; Fragile X mental retardation protein; Learning; Local translation; Olfactory bulb; Structural plasticity