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The Journal of Neuroscience, March 21, 2007, 27(12):3120-3130; doi:10.1523/JNEUROSCI.0054-07.2007

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Cellular/Molecular
Fragile X Mental Retardation Protein Induces Synapse Loss through Acute Postsynaptic Translational Regulation

Brad E. Pfeiffer and Kimberly M. Huber

Center for Basic Neuroscience, Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Correspondence should be addressed to Kimberly Huber, Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9111. Email: Kimberly.Huber{at}UTSouthwestern.edu

Fragile X syndrome, as well as other forms of mental retardation and autism, is associated with altered dendritic spine number and structure. Fragile X syndrome is caused by loss-of-function mutations in Fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates protein synthesis in vivo. It is unknown whether FMRP plays a direct, cell-autonomous role in regulation of synapse number, function, or maturation. Here, we report that acute postsynaptic expression of FMRP in Fmr1 knock-out (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, neurons endogenously expressing FMRP (wild-type) have fewer synapses than neighboring Fmr1 KO neurons. An intact K homology domain 2 (KH2) RNA-binding domain and dephosphorylation of FMRP at S500 were required for the effects of FMRP on synapse number, indicating that FMRP interaction with RNA and translating polyribosomes leads to synapse loss.

Key words: Fragile X syndrome; FMRP; hippocampus; synapse; pruning; translation

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Received Jan. 5, 2007; revised Jan. 30, 2007; accepted Feb. 1, 2007.

Correspondence should be addressed to Kimberly Huber, Center for Basic Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9111. Email: Kimberly.Huber{at}UTSouthwestern.edu

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