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Séminaire - Isabelle Caillé Local translation and adult neurogenesis

Abstract :


 Dendritic local translation is a major determinant of the synaptic plasticity underlying learning and memory.
The olfactory bulb (OB) is submitted to a high level of plasticity, including the constant replacement of some of its neurons during adulthood. We are interested in the role of local translation in olfactory plasticity and in particular adult neurogenesis. CamKIIα (Calcium Calmodulin dependent Kinase II) is a key player in synaptic plasticity, known to be locally translated in the hippocampus. In the OB, we have shown that CamKIIα is exclusively expressed by granule cells, which are the cells constantly replaced during adulthood. Its mRNA is dendritically localized, locally translated and its transport is strongly regulated by olfactory activity (1).

The fragile X mental retardation protein (FMRP) is the protein whose absence, due to silencing of the Fmr1 gene, leads to the Fragile X syndrome (FXS) in humans, the first cause of hereditary mental retardation. FMRP is an mRNA binding protein, which regulates the local translation of its target mRNAs including CamKIIα. We have previously shown that FMRP regulates the morphological integration of adult-born neurons in the OB (2). Using an olfactory perceptual task, which requires adult-born neurons in the OB, and conditional genetic ablation of FMRP in adult-born neurons, we show that learning induces profound FMRP-dependent changes in their dendritic architecture. Learning defects consecutive to the loss of FMRP can be rescued by an mGLUR5 antagonist, providing mechanistic ground to the current therapeutic use of this agent in FXS. Importantly, learning triggers an FMRP-dependent increase of local dendritic translation of αCaMKII mRNA in new neurons, which is necessary for learning and associated structural modifications.

Our results strongly suggest that FMRP mediates structural plasticity of OB adult-born neurons to support olfactory learning through αCaMKII local translation (3). This reveals a new role of dendritic local translation in learning-induced structural plasticity, necessary for dendrite morphogenesis and spine production. This might be of clinical relevance for the understanding of critical periods disruption in autism spectrum disorder patients, among which FXS is the primary monogenic cause.

Selected publications

1.Neant-Fery M, Peres E, Nasrallah C, Kessner M, Gribaudo S, Greer C, et al. (2012): A role for dendritic translation of CaMKIIalpha mRNA in olfactory plasticity. PLoS One. 7:e40133.

2.Scotto-Lomassese S, Nissant A, Mota T, Neant-Fery M, Oostra BA, Greer CA, et al. (2011): Fragile X Mental Retardation Protein Regulates New Neuron Differentiation in the Adult Olfactory Bulb. J Neurosci. 31:2205-2215.

3.L. Daroles, S. Gribaudo, M. Doulazmi, S. Scotto-Lomassese, C. Dubacq, N. Mandairon, C.A. Greer, A. Didier, A. Trembleau and I. Caillé: FMRP and dendritic local translation of αCaMKII mRNA are required for the structural plasticity underlying olfactory learning. In revision, Biological Psychiatry