Fragile X Mental Retardation Protein Induces Synapse Loss Through Acute Postsynaptic Translational Regulation

Date

2009-01-14

Authors

Pfeiffer, Brad Erich

Journal Title

Journal ISSN

Volume Title

Publisher

Abstract

Fragile X Syndrome (FXS) is the most common form of inherited mental retardation. The root cause of FXS is loss of the function of a single protein: the Fragile X Mental Retardation Protein (FMRP). FMRP is an RNA-binding protein that plays a complex role in translational regulation. FMRP may be an important regulator of dendritic protein synthesis, which occurs at or near synapses in response to synaptic activity. Many types of long-term synaptic change require local protein synthesis for their induction and/or maintenance, and several protein synthesis-dependent forms of synaptic plasticity are altered in the absence of FMRP. Both human FXS patients and mice lacking FMRP (Fmr1-KO mice) display increased numbers of dendritic spines, the primary sites of excitatory synaptic connections. In addition to increased numbers, the spines of FXS patients and Fmr1-KO mice appear morphologically immature. It was unknown whether FMRP plays a direct, cell-autonomous role in the regulation of synapse number or function. Moreover, the mechanisms through which FMRP might govern neuronal function or number were unclear. I report that acute postsynaptic expression of FMRP in Fmr1-KO neurons results in a decrease in the number of functional and structural synapses without an effect on their synaptic strength or maturational state. Similarly, wild-type neurons endogenously expressing FMRP have fewer synapses than neighboring Fmr1-KO neurons, indicating a clear role for FMRP in the regulation of synapse number. An intact K homology 2 (KH2) RNA-binding domain and dephosphorylation of FMRP at S500 are required for the effects of FMRP on synapse number, indicating that FMRP-dependent translation of mRNA targets of FMRP leads to synapse loss. Furthermore, I demonstrate novel phenotypic interactions of FMRP with the transcription factor MEF2. MEF2 activity in wild-type neurons induces robust synapse loss; however, MEF2 fails to decrease synapse number in Fmr1-KO neurons. A dominant-negative form of MEF2 increases synapse number in WT, but not Fmr1-KO neurons. Finally, when co-expressed with a dominant negative form of MEF2, FMRP fails to induce synapse loss in Fmr1-KO neurons. These data represent novel mechanisms through which FMRP regulates neuronal function and suggest novel therapeutic targets and strategies for FXS treatment.

General Notes

Table of Contents

Citation

Related URI