Local translation of actin-binding proteins in the healthy and diseased central nervous system

Abstract

Long-lasting modifications of synaptic efficacy of single synapses are believed to represent the cellular correlates of learning and memory formation and depend on the global and local translation of pre-existing mRNAs. These local translation events allow synapses to autonomously and specifically change their structural and functional properties on a rapid time scale, a phenomenon that depends on a fast remodeling of the actin cytoskeleton mediated by actin-binding proteins (ABPs). In the Fragile X Syndrome (FXS), where the Fragile X mental retardation protein 1 as a regulator of mRNA transport and local translation is absent, alterations in synapse structure and function indeed point towards dysregulated actin dynamics. Therefore, this study aimed at analyzing the role of dynamic actin and ABPs as an underlying cause of synapse pathology in FXS. In experiments involving NMDAR-dependent long-term potentiation (LTP; glycine-mediated) or mGluR-dependent long-term depression (LTD; DHPG-mediated) combined with Fluorescence in situ Hybridization, this work provides evidence that the mRNAs of the ABPs Profilin 1, Profilin 2a and Cofilin 1 (Cof1) are not only localized in dendrites of hippocampal neurons but also that ABP mRNA localization is mediated in an activity-dependent manner. In addition, Fluorescence Recovery after Photobleaching of membrane-targeted eGFP fused to the 3’UTR of Cof1 revealed that the local translation of Cof1 is modulated in an activity-dependent manner as well. Intriguingly, this study shows that in the mouse model of FXS (fmr1 KO), these activity-dependent modulations of ABP mRNAs are absent and in case of NMDAR-dependent LTP, these defects are additionally accompanied by a complete loss of structural plasticity. Most importantly, this structural plasticity defect could be rescued by mimicking Cof1 modulation of WT neurons, thereby directly attributing plasticity deficits in FXS to a dysregulation of ABPs. In summary, this work shows for the first time that the local translation of ABPs is mediated in an activity-dependent manner, a modulation that appears to be crucial for the proper induction of NMDAR-dependent LTP as well as mGluR-dependent LTD in hippocampal neurons. In addition, this study proposes a causal relationship between dysregulated actin dynamics, derived from alterations in the modulation of local ABP synthesis and local ABP mRNA availability, and synapse pathologies as well as learning deficits in the mouse model of FXS.