Abstract
Mir-132 is a neuronal activity-regulated microRNA that controls the morphology of dendritic spines and neuronal transmission. Similar activities have recently been attributed to matrix metalloproteinase-9 (MMP-9), an extrasynaptic protease. In the present study, we provide evidence that miR-132 directly regulates MMP-9 mRNA in neurons to modulate synaptic plasticity. With the use of luciferase reporter system, we show that miR-132 binds to the 3’UTR of MMP-9 mRNA to regulate its expression in neurons. The overexpression of miR-132 in neurons reduces the level of endogenous MMP-9 protein secretion. In synaptoneurosomes, metabotropic glutamate receptor (mGluR)-induced signaling stimulates the dissociation of miR-132 from polyribosomal fractions and shifts it towards the messenger ribonucleoprotein (mRNP)-containing fraction. Furthermore, we demonstrate that the overexpression of miR-132 in the cultured hippocampal neurons from Fmr1 KO mice that have increased synaptic MMP-9 level provokes enlargement of the dendritic spine heads, a process previously implicated in enhanced synaptic plasticity. We propose that activity-dependent miR-132 regulates structural plasticity of dendritic spines through matrix metalloproteinase 9.
Highlights
Reorganization of the neuronal networks supports physiological phenomena of learning and memory, as well as major neuropsychiatric pathologies, such as epilepsy, addiction, schizophrenia, to name just a few
We provide evidence for miR-132-dependent regulation of matrix metalloproteinase-9 (MMP-9) mRNA in neurons that result in structural changes of dendritic spines
fragile X mental retardation protein (FMRP) can bind MMP-9 mRNA [22]. miR-132 and MMP-9 mRNA were not studied together in the context of FMRP; these findings suggested that they could be a part of the same protein-RNA complex
Summary
Reorganization of the neuronal networks supports physiological phenomena of learning and memory, as well as major neuropsychiatric pathologies, such as epilepsy, addiction, schizophrenia, to name just a few. MicroRNAs have emerged as important regulators of molecular events occurring at the synapses, and being responsible for their plastic changes. MicroRNAs (miRNAs) are small, ~21-nt-long RNAs that post-transcriptionally regulate gene expression in eukaryotes. Many studies confirmed the presence of microRNAs in the dendrites and synapses where they are believed to fine-tune the local expression of synaptic proteins [4]. Mir-132 is a neuronal activity-regulated microRNA, which expression is induced by plasticityimplicated transcription factor CREB—cAMP response element-binding protein [5]. MiR-132 is present in the dendrites and at synapses [10,11,12], what makes it a potential unique regulator of locally translated synaptic proteins. When ectopically expressed in hippocampal neurons, miR-132 induces enlargement of dendritic spines [18, 6]
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