Dendritic mRNA transport and local translation in the postsynaptic compartment play an important role in synaptic plasticity, learning and memory. Local protein synthesis at the synapse has to be ...precisely orchestrated by a plethora of factors including RNA binding proteins as well as microRNAs, an extensive class of small non-coding RNAs. By binding to complementary sequences in target mRNAs, microRNAs fine-tune protein synthesis and thereby represent critical regulators of gene expression at the post-transcriptional level. Research over the last years identified an entire network of dendritic microRNAs that fulfills an essential role in synapse development and physiology. Recent studies provide evidence that these small regulatory molecules are highly regulated themselves, at the level of expression as well as function. The importance of microRNAs for correct function of the nervous system is reflected by an increasing number of studies linking dysregulation of microRNA pathways to neurological disorders. By focusing on three extensively studied examples (miR-132, miR-134, miR-138), this review will attempt to illustrate the complex regulatory roles of dendritic microRNAs at the synapse and their implications for pathological conditions.
Specific microRNAs (miRNAs), including miR-134, localize to neuronal dendrites, where they control synaptic protein synthesis and plasticity. However, the mechanism of miRNA transport is unknown. We ...found that the neuronal precursor-miRNA-134 (pre-miR-134) accumulates in dendrites of hippocampal neurons and at synapses in vivo. Dendritic localization of pre-miR-134 is mediated by the DEAH-box helicase DHX36, which directly associates with the pre-miR-134 terminal loop. DHX36 function is required for miR-134-dependent inhibition of target gene expression and the control of dendritic spine size. Dendritically localized pre-miR-134 could provide a local source of miR-134 that can be mobilized in an activity-dependent manner during plasticity.
Adaptation to different levels of illumination is central to the function of the retina. Here, we demonstrate that levels of the miR-183/96/182 cluster, miR-204, and miR-211 are regulated by ...different light levels in the mouse retina. Concentrations of these microRNAs were downregulated during dark adaptation and upregulated in light-adapted retinas, with rapid decay and increased transcription being responsible for the respective changes. We identified the voltage-dependent glutamate transporter
Slc1a1 as one of the miR-183/96/182 targets in photoreceptor cells. We found that microRNAs in retinal neurons decay much faster than microRNAs in nonneuronal cells. The high turnover is also characteristic of microRNAs in hippocampal and cortical neurons, and neurons differentiated from ES cells in vitro. Blocking activity reduced turnover of microRNAs in neuronal cells while stimulation with glutamate accelerated it. Our results demonstrate that microRNA metabolism in neurons is higher than in most other cells types and linked to neuronal activity.
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► Several miRNAs are transcriptionally upregulated by light in mouse retinal neurons ► Glutamate transporter SLC1A1 is one of the targets of the light-regulated miRNAs ► miRNAs in retinal and nonretinal neurons decay much faster than in other cells ► Blocking action potentials or glutamate receptors strongly affects miRNA turnover
The E3 ubiquitin ligase Ube3a is an important regulator of activity-dependent synapse development and plasticity. Ube3a mutations cause Angelman syndrome and have been associated with autism spectrum ...disorders (ASD). However, the biological significance of alternative Ube3a transcripts generated in mammalian neurons remains unknown. We report here that Ube3a1 RNA, a transcript that encodes a truncated Ube3a protein lacking catalytic activity, prevents exuberant dendrite growth and promotes spine maturation in rat hippocampal neurons. Surprisingly, Ube3a1 RNA function was independent of its coding sequence but instead required a unique 3' untranslated region and an intact microRNA pathway. Ube3a1 RNA knockdown increased activity of the plasticity-regulating miR-134, suggesting that Ube3a1 RNA acts as a dendritic competing endogenous RNA. Accordingly, the dendrite-growth-promoting effect of Ube3a1 RNA knockdown in vivo is abolished in mice lacking miR-134. Taken together, our results define a noncoding function of an alternative Ube3a transcript in dendritic protein synthesis, with potential implications for Angelman syndrome and ASD.
microRNAs (miRNAs) have emerged as critical regulators of neuronal dendrite development. Specific precursor (pre-)miRNAs are actively transported to dendrites, but whether this process is regulated ...by neuronal activity and involved in activity-dependent dendritogenesis is unknown. Here we show that BDNF, a neurotrophin that is released in response to increased neuronal activity, promotes dendritic accumulation of pre-miR-134. Dendritic accumulation, but not transcription of pre-miR-134, is abrogated by treatment of neurons with the NMDA receptor (NMDAR) antagonist APV. Furthermore, APV interferes with BDNF-mediated repression of the known miR-134 target Pumilio 2 (Pum2) in a miR-134 binding site-specific manner. At the functional level, both APV treatment and knockdown of the pre-miR-134 transport protein DHX36 antagonize BDNF-induced dendritogenesis. These effects are likely mediated by reduced dendritic miR-134 activity, since both transfection of a synthetic miR-134 duplex or of a dendritically targeted pre-miR-134-181a chimera rescues BDNF-dependent dendritogenesis in the presence of APV. In conclusion, we have identified a novel NMDAR-dependent mechanism involved in the activity-dependent control of miRNA function during neuronal development.
Synaptic downscaling is a homeostatic mechanism that allows neurons to reduce firing rates during chronically elevated network activity. Although synaptic downscaling is important in neural circuit ...development and epilepsy, the underlying mechanisms are poorly described. We performed small RNA profiling in picrotoxin (PTX)‐treated hippocampal neurons, a model of synaptic downscaling. Thereby, we identified eight microRNAs (miRNAs) that were increased in response to PTX, including miR‐129‐5p, whose inhibition blocked synaptic downscaling in vitro and reduced epileptic seizure severity in vivo. Using transcriptome, proteome, and bioinformatic analysis, we identified the calcium pump Atp2b4 and doublecortin (Dcx) as miR‐129‐5p targets. Restoring Atp2b4 and Dcx expression was sufficient to prevent synaptic downscaling in PTX‐treated neurons. Furthermore, we characterized a functional crosstalk between miR‐129‐5p and the RNA‐binding protein (RBP) Rbfox1. In the absence of PTX, Rbfox1 promoted the expression of Atp2b4 and Dcx. Upon PTX treatment, Rbfox1 expression was downregulated by miR‐129‐5p, thereby allowing the repression of Atp2b4 and Dcx. We therefore identified a novel activity‐dependent miRNA/RBP crosstalk during synaptic scaling, with potential implications for neural network homeostasis and epileptogenesis.
Synopsis
A systematic approach using small RNA and mRNA profiling in combination with proteomics is used to delineate post‐transcriptional regulatory pathways involved in synaptic scaling. This led to the identification of a pathway consisting of the miRNA miR‐129‐5p and the RNA‐binding protein Rbfox that controls excitatory synapse function in neurons and epileptic seizure activity in the brain.
8 microRNAs, including miR‐129‐5p, are upregulated during homeostatic synaptic downscaling in hippocampal neurons.
miR‐129‐5p inhibition blocks synaptic downscaling in vitro and kainic acid‐induced epileptic seizures in vivo.
A combination of transcriptomics, proteomics and bioinformatics was used to identify miR‐129‐5p target mRNAs, including Atp2b4, Dcx and Rbfox1/3.
Activity‐dependent downregulation of Rbfox1 by miR‐129‐5p is required for the repression of synaptic genes during homeostatic synaptic downscaling.
Combining miRNA and mRNA profiling with proteomics reveals roles for miR‐129‐5p and the RNA‐binding protein Rbfox in excitatory synapse function and epileptic seizure.
The proper development and function of neuronal circuits rely on a tightly regulated balance between excitatory and inhibitory (E/I) synaptic transmission, and disrupting this balance can cause ...neurodevelopmental disorders, for example, schizophrenia. MicroRNA-dependent gene regulation in pyramidal neurons is important for excitatory synaptic function and cognition, but its role in inhibitory interneurons is poorly understood. Here, we identify
as a regulator of short-term memory and inhibitory synaptic transmission in the mouse hippocampus. Sponge-mediated
inactivation specifically in mouse parvalbumin (PV)-expressing interneurons impairs spatial recognition memory and enhances GABAergic synaptic input onto pyramidal neurons. Cellular and behavioral phenotypes associated with
inactivation are paralleled by an upregulation of the schizophrenia (SCZ)-associated
, which we validated as a direct
target gene. Our findings suggest that
is a critical regulator of PV interneuron function in mice, with implications for cognition and SCZ. More generally, they provide evidence that microRNAs orchestrate neural circuit development by fine-tuning both excitatory and inhibitory synaptic transmission.
MicroRNAs have emerged as crucial regulators of neuronal function, suggesting that aberrant microRNA expression might contribute to pathologies of the nervous system. In this issue of The EMBO ...Journal, Emde et al () report a global decrease in microRNAs as common hallmark of different forms of amyotrophic lateral sclerosis (ALS). Strikingly, enhancing microRNA biogenesis has beneficial effects on the neuromuscular function in mouse models of ALS. Thus, the microRNA pathway represents a promising novel target for therapeutic intervention in neurodegeneration.
A new study finds a global decrease in microRNA levels to be a common hallmark of amyotrophic lateral sclerosis (ALS) and shows that enhancing microRNA biogenesis has beneficial effects on the neuromuscular function in mouse models of ALS.
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