Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132
Neuron. 2010 Feb 11;65(3):373-84.
|Type of Publication:||Journal Article|
The most common inherited cause of mental retardation, Fragile X syndrome (FXS) is an X-linked disorder affecting about 1 in 3600 males and 1 in 5000 females. In addition to moderate to severe mental retardation, FXS is often associated with autistic behavior and epileptic seizures. The main cause of FXS is a trinucleotide expansion in the FMR1 gene that results in transcriptional silencing of FMRP (Fragile X mental retardation protein) expression. FMRP contains multiple RNA-binding domains and is widely thought to function as a translational suppressor of specific mRNAs. Moreover, FMRP is biochemically and genetically linked to the microRNA pathway. We show that a variety of microRNAs, short non-coding RNAs that suppress translation of specific mRNAs, are biochemically associated with FMRP in mouse brain. Two of these microRNAs strongly affect synaptic structure and function: miR-125b promotes thinner spines and weaker synapses while miR-132 induces opposite changes. miR-125b also suppresses expression of the NMDA receptor subunit NR2A via its 3’ untranslated region. Both of these effects involve a functional interaction between these microRNAs and FMRP. Because NMDA receptor subunit composition profoundly affects synaptic plasticity, the cellular correlate of learning and memory, these observations have implications for the pathophysiology of Fragile X Syndrome, in which plasticity is altered.