Mutations in the RNA-binding protein fragile X mental retardation protein (FMRP) underlie the neuronal dysfunction observed in Fragile X syndrome (FXS). Gaining an understanding of the normal role of FMRP in neuronal function is essential in order to understand the pathogenesis of FXS. A new study shows that FMRP influences synapse number by regulating translation in postsynaptic neurons.
Pfeiffer and Huber investigated the effects of transfection of human FMR1 in hippocampal slice cultures prepared from Fmr1−/− mice. Expression of FMR1 resulted in a reduction in the amplitude of evoked excitatory postsynaptic currents (EPSCs), demonstrating altered synaptic transmission.
This effect could be the result of reduced synaptic strength, presynaptic glutamate release probability or synapse number. The authors showed that neither the amplitude of spontaneous miniature EPSCs — a measure of synaptic strength — nor the ability to induce paired-pulse facilitation — an indicator of presynaptic release probability — were altered, suggesting that the effects of FMRP were due to a decrease in synapse number. This was supported by the demonstration of an increase in failures of synaptic transmission when small numbers of axons were stimulated and by reduced immunostaining for synaptic proteins in dissociated hippocampal cultures. Wild-type hippocampal cultures also had fewer synapses compared to Fmr1 knockouts, showing that the effects of exogenous FMRP are mirrored by those of the endogenous protein.
How does FMRP alter synapse number? The authors showed that a mutation in one of the FMRP domains that binds to mRNA and polyribosomes to regulate protein translation eliminated the effects of FMRP on synapse number. The ability of FMRP to stimulate protein translation is known to be reduced by phosphorylation. The authors showed that a mutant FMRP that mimicked phosphorylation of the protein eliminated the reduction of synapse number observed when wild-type FMRP was transfected, confirming that FMRP alters synaptic function through its ability to regulate protein translation.
This study provides evidence that the normal roles of FMRP include the control of synapse number through its effects on protein translation, giving us a greater understanding of the role of this protein in neuronal function. Further work will be required to determine which particular mRNAs' translation are regulated by FMRP to alter synapse number.
ORIGINAL RESEARCH PAPER
Pfeiffer, B. E. & Huber, K. M. Fragile X mental retardation protein induces synapse loss through acute postsynaptic translational regulation. J. Neurosci. 27, 3120–3130 (2007)
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Whalley, K. The X factor. Nat Rev Neurosci 8, 325 (2007). https://doi.org/10.1038/nrn2136