title: Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome.
abstract: Fragile X syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, fragile X mental retardation protein. Fmr1 global knockout (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS.
  
  
  
  Taking advantage of the Cre-lox system, we generated and characterized mice in which fragile X mental retardation protein is selectively deleted or exclusively expressed in astrocytes. We performed in vivo two-photon imaging to track spine dynamics/morphology along dendrites of neurons in the motor cortex and examined associated behavioral defects.
  
  
  
  We found that adult astrocyte-specific Fmr1 KO mice displayed increased spine density in the motor cortex and impaired motor-skill learning. The learning defect coincided with a lack of enhanced spine dynamics in the motor cortex that normally occurs in response to motor skill acquisition. Although spine density was normal at 1 month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, fragile X mental retardation protein expression in only astrocytes was insufficient to rescue most spine or behavioral defects.
  
  
  
  Our work suggests a joint astrocytic-neuronal contribution to FXS pathogenesis and reveals that heightened spine formation during adolescence precedes the overabundance of spines and behavioral defects found in adult Fmr1 KO mice.
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hodges
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Xinzhu
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Gilmore
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Bennett
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Tjia
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Perna
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Chia-Chien
authors.initials: CC
authors.lastname: Chen
authors.affiliation: The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences (CAS), Shenzhen 518055, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Ju
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Molecular, Cell and Developmental Biology, University of California Santa Cruz, Santa Cruz, CA 95064, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zuo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology*; D049229:Dendritic Spines / Q000502:physiology*; D004195:Disease Models, Animal; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000503:physiopathology*; D007858:Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009044:Motor Cortex / Q000503:physiopathology*; D009048:Motor Skills / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse
keywords: Astrocytes; Dendritic spines; Fmr1; Fragile X syndrome; Motor cortex; Motor learning