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

Biol Psychiatry. 2016 Jul 15;80(2):149-159. doi: 10.1016/j.biopsych.2015.07.023. Epub 2015 Aug 7.

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.

Keywords: Adult neurogenesis; Fragile X mental retardation protein; Learning; Local translation; Olfactory bulb; Structural plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autism Spectrum Disorder / genetics
  • Autism Spectrum Disorder / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Dendrites / metabolism*
  • Dendritic Spines / metabolism
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein / metabolism*
  • Fragile X Syndrome / genetics
  • Fragile X Syndrome / metabolism
  • Learning / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurogenesis / genetics
  • Neurogenesis / physiology*
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology*
  • Olfactory Perception / physiology*
  • RNA, Messenger

Substances

  • Fmr1 protein, mouse
  • RNA, Messenger
  • Fragile X Mental Retardation Protein
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Camk2a protein, mouse