MicroRNAs (miRNAs) are small non-coding RNAs that inhibit protein translation by binding to the 3′ untranslated region (3′ UTR) of target mRNAs. miRNAs are abundant in the brain, with the challenge being to identify their roles and targets in specific neuronal functions. Homeostatic synaptic scaling is a form of plasticity by which neurons make compensatory adjustments to the strength of excitatory synapses according to their activity level. Notably, postsynaptic AMPA receptors (AMPARs), which are the major effectors of communication at glutamatergic synapses, are upregulated following activity blockade. In a well-characterized procedure, treatment of hippocampal neurons with tetrodotoxin (TTX, to prevent action potentials) and AP5 (to further block NMDA receptor–mediated miniature synaptic transmission) increases the expression of GluA1 homomeric AMPARs through local translation of GluA1 mRNAs present in dendrites.
We showed that miR-92a strongly repressed the translation of GluA1 receptors by binding the 3′ untranslated region of rat GluA1 mRNA. In addition, miR-92a was downregulated in rat hippocampal neurons after treatment with TTX and AP5. Deleting the seed region for miR-92a in GluA1 (that is the nucleotide sequence to which miR-92a binds) or overexpressing miR-92a blocked homeostatic scaling as assessed by immunostaining and electrophysiological recordings.
Together, our data indicate that miR-92a selectively regulates GluA1 translation and is necessary for the synaptic scaling associated with incorporation of new GluA1 receptors during activity blockade in hippocampal neurons. This type of regulation may cooperate with other mechanisms underlying synaptic scaling, including retinoic acid signaling, β-CamKII activation and the miR-485 presynaptic target SVA2. A question for the future is how activity deprivation alters the level of miRNAs upstream of their effects on mRNA translation.
1. Univ. Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France
2. CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33000 Bordeaux, France