Fragile X Mental Retardation Protein Induces Synapse Loss Through Acute Postsynaptic Translational Regulation
| dc.contributor.advisor | Huber, Kimberly | en |
| dc.creator | Pfeiffer, Brad Erich | en |
| dc.date.accessioned | 2010-07-12T18:23:24Z | en |
| dc.date.accessioned | 2014-02-19T22:02:12Z | |
| dc.date.available | 2010-07-12T18:23:24Z | en |
| dc.date.available | 2014-02-19T22:02:12Z | |
| dc.date.issued | 2009-01-14 | en |
| dc.description.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. | en |
| dc.format.digitalOrigin | born digital | en |
| dc.format.medium | Electronic | en |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.other | 759935314 | en |
| dc.identifier.uri | http://hdl.handle.net/2152.5/538 | en |
| dc.language.iso | en | en |
| dc.subject | Fragile X Mental Retardation Protein | en |
| dc.subject | Synapses | en |
| dc.subject | RNA-Binding Proteins | en |
| dc.title | Fragile X Mental Retardation Protein Induces Synapse Loss Through Acute Postsynaptic Translational Regulation | en |
| dc.type.genre | dissertation | en |
| dc.type.material | Text | en |
| thesis.date.available | 2010-01-14 | en |
| thesis.degree.department | en | |
| thesis.degree.discipline | Neuroscience | en |
| thesis.degree.grantor | Graduate School of Biomedical Sciences | en |
| thesis.degree.level | Ph.D. | en |
| thesis.degree.name | Doctor of Philosophy | en |