Laura Daroles1, Simona Gribaudo1, Mohamed Doulazmi1, Sophie Scotto-Lomassese1, Caroline Dubacq1, Nathalie Mandairon2, Charles August Greer3, Anne Didier2, Alain Trembleau1, Isabelle Caillé4. 1. Sorbonne Universités, Université Pierre et Marie Curie Univ Paris 06, Centre National de la Recherche Scientifique UMR8246, INSERM U1130, IBPS, Neuroscience Paris Seine, France. 2. Université Lyon1, CNRS UMR 5292, INSERM U1028, Centre de Recherche en Neurosciences de Lyon. 3. Yale University School of Medicine, Department of Neurosurgery, New Haven, Connecticut. 4. 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.
Abstract
BACKGROUND: 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.
BACKGROUND: 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 disorderpatients, among which fragile X syndrome is the primary monogenic cause.
Authors: Sushmitha S Purushotham; Neeharika M N Reddy; Michelle Ninochka D'Souza; Nilpawan Roy Choudhury; Anusa Ganguly; Niharika Gopalakrishna; Ravi Muddashetty; James P Clement Journal: Exp Brain Res Date: 2022-09-05 Impact factor: 2.064
Authors: Sabiha Abekhoukh; H Bahar Sahin; Mauro Grossi; Samantha Zongaro; Thomas Maurin; Irene Madrigal; Daniele Kazue-Sugioka; Annick Raas-Rothschild; Mohamed Doulazmi; Pilar Carrera; Andrea Stachon; Steven Scherer; Maria Rita Drula Do Nascimento; Alain Trembleau; Ignacio Arroyo; Peter Szatmari; Isabel M Smith; Montserrat Milà; Adam C Smith; Angela Giangrande; Isabelle Caillé; Barbara Bardoni Journal: Dis Model Mech Date: 2017-02-09 Impact factor: 5.758