Abstract
Fragile X syndrome (FXS) is a neurodevelopmental disorder that represents a common cause of intellectual disability and is a variant of autism spectrum disorder (ASD). Studies that have searched for similarities in syndromic and non-syndromic forms of ASD have paid special attention to alterations of maturation and function of glutamatergic synapses. Copy number variations (CNVs) in the loci containing genes encoding alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) subunits are associated with ASD in genetic studies. In FXS, dysregulated AMPAR subunit expression and trafficking affect neural progenitor differentiation and synapse formation and neuronal plasticity in the mature brain. Decreased expression of GluA2, the AMPAR subunit that critically controls Ca2+-permeability, and a concomitant increase in Ca2+-permeable AMPARs (CP-AMPARs) in human and mouse FXS neural progenitors parallels changes in expression of GluA2-targeting microRNAs (miRNAs). Thus, posttranscriptional regulation of GluA2 by miRNAs and subsequent alterations in calcium signaling may contribute to abnormal synaptic function in FXS and, by implication, in some forms of ASD.
Highlights
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders that are characterized by defective social interaction, impairment in verbal and nonverbal communication, repetitive and restricted behavior, and sensory abnormalities (American Psychiatric Association, 2013)
A genetic deletion that includes the GRIA2 gene encoding GluA2 is associated with autism (Ramanathan et al, 2004) and mutations of RAB39B that cause intellectual disability comorbid with autism lead to impaired transport of GluA2 to synapses and subsequent shift of alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPARs) to higher calcium permeability (Mignogna et al, 2015)
This review summarizes AMPAR alterations observed in fragile X syndrome (FXS) used as a model for studies of autism symptomatology
Summary
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders that are characterized by defective social interaction, impairment in verbal and nonverbal communication, repetitive and restricted behavior, and sensory abnormalities (American Psychiatric Association, 2013). ASD has a strong genetic component and genetic studies have implicated hundreds of genes associated with increased risk of ASD (Persico and Napolioni, 2013). Extreme locus heterogeneity in ASD suggests that an interplay of common and rare genetic variations contribute to the ASD phenotype (O’Roak et al, 2012). These findings have led to the identification of candidate pathways and functional changes involved in the pathophysiology of ASD (Pinto et al, 2010). Features of autism associate with distinct rare monogenic neurodevelopmental syndromes, including fragile X syndrome (FXS), tuberosis sclerosis, and Rett syndrome (Lintas et al, 2012)
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