Multifarious Functions of the Fragile X Mental Retardation Protein

Abstract

Fragile X syndrome (FXS), a heritable intellectual and autism spectrum disorder (ASD), results from the loss of Fragile X mental retardation protein (FMRP). This neurodevelopmental disease state exhibits neural circuit hyperconnectivity and hyperexcitability. Canonically, FMRP functions as an mRNA-binding translation suppressor, but recent findings have enormously expanded its proposed roles. Although connections between burgeoning FMRP functions remain unknown, recent advances have extended understanding of its involvement in RNA, channel, and protein binding that modulate calcium signaling, activity-dependent critical period development, and the excitation-inhibition (E/I) neural circuitry balance. In this review, we contextualize 3 years of FXS model research. Future directions extrapolated from recent advances focus on discovering links between FMRP roles to determine whether FMRP has a multitude of unrelated functions or whether combinatorial mechanisms can explain its multifaceted existence.

Keywords: Fragile X syndrome (FXS); activity-dependent critical period; autism spectrum disorder (ASD); synapse; translation regulation.

Figure 1. FMRP roles in RNA- and channel-binding at the neuronal synapse

Activity-dependent functions of FMRP in RNA-binding translation regulation and direct channel-binding activity regulation. In the uncoupled mechanism (left), RNA- and channel-binding roles are unrelated, representing two evolutionarily divergent functions. In the coupled mechanism (right), channel-binding is an integral activity-sensing step in the translational regulation of FMRP-bound transcripts.