Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us

Abstract

The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome

“…These findings are consistent with the reduction of protein synthesis observed at the synapses of the Fmr1 KO/ Adam10 Het and Fmr1 KO/App Het mice ( Figures 5B and 5E). Finally, we monitored the effect of the peptide on working memory (T-maze) and hyperactivity (open field) ( Figures 6G and 6H), two behavioral features that have been consistently found altered in FXS mice (Santos et al, 2014). Fmr1 KO mice move faster and travel a longer distance in the open field, and they fail more in the spontaneous alternation in the T-maze (Santos et al, 2014).…”

“…Finally, we monitored the effect of the peptide on working memory (T-maze) and hyperactivity (open field) ( Figures 6G and 6H), two behavioral features that have been consistently found altered in FXS mice (Santos et al, 2014). Fmr1 KO mice move faster and travel a longer distance in the open field, and they fail more in the spontaneous alternation in the T-maze (Santos et al, 2014). Nest building is a social behavior in mice impaired in Fragile X and other models of autism (Udagawa et al, 2013).…”

“…At the cellular level, FXS neurons have an increased number of dendritic spines that appear long, thin, and tortuous (Hinton et al, 1991;Irwin et al, 2001). The mouse model of FXS (Fmr1 knockout [KO]) exhibits morphological, synaptic, and behavioral alterations similar to human patients (Bakker, 1994;Comery et al, 1997;Huber et al, 2002;Santos et al, 2014).…”

Intranasal siRNA administration reveals IGF2 deficiency contributes to impaired cognition in Fragile X syndrome mice

“…Several reports showed that nanoparticle-linked siRNA can be delivered into the brain by intranasal administration to knock down target proteins (26,27). We embarked on an investigation using this approach to target GSK3β as a potential therapeutic intervention for the severe intellectual disability of Fragile X syndrome (28). For this, we used 2 mouse models of Fragile X syndrome that display impaired cognition, Fmr1 -/-mice and GSK3 knockin mice, because GSK3 is abnormally active in Fmr1 -/-mouse hippocampus and other regions, and peripheral administration of GSK3 inhibitors ameliorate several impairments in learning and memory in Fmr1 -/-mice (29)(30)(31).…”

Temporal course of gene expression during motor memory formation in primary motor cortex of rats

“…Furthermore, MAGOH is involved in regulating division of neuronal stem cells (Silver, Watkins-Chow, Schreck, Pierfelice, Larson, Burnetti, Liaw, Myung, Walsh, Gaiano, and Pavan, 2010). The fragile X mental retardation gene (FMR1) codes for FMRP that has four RNA-binding domains that differentially affect transport, stability and translation of mRNA (Santos, Kanellopoulos, and Bagni, 2014). Dysfunction of FMRP leads to a dysregulation of translation, i.e.…”