Precise control of protein translation in neurons, particularly translation occurring in dendrites near synaptic sites, is critical for the proper regulation of synaptic strength. The most direct way to affect the strength of glutamatergic synapses is to alter the abundance of AMPA-type glutamate receptors (AMPARs). Here I demonstrate the critical role that two separate translational regulators play in controlling the translation of the AMPAR subunit GluR1, both under steady-state conditions and during synaptic plasticity.
Homeostatic synaptic plasticity adjusts the strength of synapses during global changes in neural activity, thereby stabilizing the overall activity of neural networks. Suppression of synaptic activity increases synaptic strength by inducing synthesis of retinoic acid (RA), which activates postsynaptic synthesis and insertion of AMPARs. Here, I show that the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein that regulates dendritic protein synthesis, is essential for increases in synaptic strength induced by RA or by blockade of neural activity in the mouse hippocampus. Although activity-dependent RA synthesis is maintained in Fmr1 knockout neurons, RA-dependent dendritic translation of GluR1-type AMPARs is impaired. Intriguingly, FMRP is only required for the form of homeostatic plasticity which is dependent on both RA signaling and local protein synthesis. Expression of FMRP in knockout neurons reduced the total, surface, and synaptic levels of AMPARs, implying a role for FMRP in regulating AMPAR abundance. Critically, postsynaptic expression in knockout neurons of wild-type FMRP, but not two different mutant forms of the protein, was able to fully restore synaptic scaling.
microRNAs (miRNAs) are small RNA molecules which bind to the untranslated regions of mRNAs and inhibit translation. Using a bioinformatics approach, I identified a pair of miRNAs, miR-96 and miR-182, which bind specifically to a known sequence in the GluR1 mRNA and prevent its translation. When overexpressed, these miRNAs reduce total and extrasynaptic levels of GluR1 protein in neurons, and prevent the induction of homeostatic plasticity by activity blockade. Both miR-96 and miR-182 are expressed in cortex throughout postnatal development, although we were unable to detect activity-dependent changes in the abundance of either miRNA. Attempted knockdown of both miRNAs revealed no significant effect on the abundance of GluR1 or the ability of neurons to undergo homeostatic plasticity.
Taken together, these data offer significant insight into the regulation of local translation of glutamate receptors at the synapse, particularly during specific forms of synaptic plasticity. These results also suggest that some of the symptoms of Fragile-X syndrome may be attributed to defects in the induction of homeostatic plasticity.