Final Report Summary - NEUROMIR (microRNA function in homeostatic plasticity in the mammalian brain)
In the mammalian brain, neurons are intricately connected within neural networks by billions of specialized junctions known as synapses. The correct formation and functioning of neural networks is of critical importance for higher cognitive functions, such as learning and memory. On the other hand, defects in neural network homeostasis are associated with neurodevelopmental and psychiatric conditions, including autism-spectrum disorders, intellectual disability and schizophrenia. A nested set of cellular mechanisms, commonly referred to as homeostatic plasticity, are engaged to keep neural network homeostasis. One such mechanism is homeostatic synaptic scaling, which involves a unitary decrease/increase of excitatory strength in response to chronic activity changes in prinicipal neurons of the cortex and hippocampus. Compared to classical Hebbian forms of synaptic plasticity that are involved in memory formation, relatively little is known about the molecular mechanisms underlying homeostatic synaptic scaling. In the course of this ERC project, we investigated a potential function of microRNAs in synaptic downscaling of excitatory synapses of hippocampal pyramidal neurons. microRNAs are a large family of small non-coding RNAs that act as post-transcriptional regulators of gene expression. They do so by binding to complementary nucleotide sequences within the 3’ untranslated region (UTR) of target mRNAs, which in turn results in their translational repression and/or decay. We focused on a large mammalian specific microRNA cluster consisting of >50 individual miRNAs, miR379-410. We had previously shown that specific microRNAs of this cluster, in particular miR-134, play important roles in the development and plasticity of excitatory synapses. However, a contribution of miRNA-dependent regulation to synaptic scaling had not been previously addressed.
Using chronic pharmacological blockade of synaptic inhibition in hippocampal neurons as a model for synaptic downscaling, we identified a critical function for miR-134 in the downregulation of synaptic morphology and strength. This effect was mediated by inhibition of expression of the RBP Pumilio2, which in turn controls a pathway involved in AMPA-type glutamate receptor trafficking (Fiore et al., 2014). In follow-up studies, we performed a detailed analysis of the cellular mechanisms that control miR-134 function at both the neuron-wide and synaptic level in response to neuronal activity. First, we elucidated a dendritic transport mechanism dependent on the DEAH-box helicase DHX36 that is responsible for the dendritic localization of pre-miR-134 (Bicker et al., 2013). This suggests regulated pre-miR-134 local processing at synapses as one potential mechanism to increase miR-134 activity during scaling. Second, we discovered a coding-independent function of a dendritic RNA, Ube3a-1, in the regulation of local miR-134 activity (Valluy et al., 2015). Ube3a-1 works by sequestering miR379-410 microRNAs, thereby relieving repression of target mRNAs that are naturally repressed by these miRNAs upon association. Third, we characterized two RBPs that enhance miR-134 repressive activity via the regulation of the miRISC core component Argonaute (Störchel et al., 2015).
Finally, at the organismic level, we obtained evidence for a physiological role of miR379-410 microRNAs in rodent behavior.
In conclusion, results from this project significantly enhanced our understanding of the molecular mechanisms engaged during homeostatic plasticity in mammalian neurons, a process that is of vital importance for the experience-dependent development and function of neural circuits. Thus, our results form the basis for future studies that will test the potential of microRNA manipulation as novel therapeutic option for diseases that are charcterized by impaired neuronal homeostasis.
Using chronic pharmacological blockade of synaptic inhibition in hippocampal neurons as a model for synaptic downscaling, we identified a critical function for miR-134 in the downregulation of synaptic morphology and strength. This effect was mediated by inhibition of expression of the RBP Pumilio2, which in turn controls a pathway involved in AMPA-type glutamate receptor trafficking (Fiore et al., 2014). In follow-up studies, we performed a detailed analysis of the cellular mechanisms that control miR-134 function at both the neuron-wide and synaptic level in response to neuronal activity. First, we elucidated a dendritic transport mechanism dependent on the DEAH-box helicase DHX36 that is responsible for the dendritic localization of pre-miR-134 (Bicker et al., 2013). This suggests regulated pre-miR-134 local processing at synapses as one potential mechanism to increase miR-134 activity during scaling. Second, we discovered a coding-independent function of a dendritic RNA, Ube3a-1, in the regulation of local miR-134 activity (Valluy et al., 2015). Ube3a-1 works by sequestering miR379-410 microRNAs, thereby relieving repression of target mRNAs that are naturally repressed by these miRNAs upon association. Third, we characterized two RBPs that enhance miR-134 repressive activity via the regulation of the miRISC core component Argonaute (Störchel et al., 2015).
Finally, at the organismic level, we obtained evidence for a physiological role of miR379-410 microRNAs in rodent behavior.
In conclusion, results from this project significantly enhanced our understanding of the molecular mechanisms engaged during homeostatic plasticity in mammalian neurons, a process that is of vital importance for the experience-dependent development and function of neural circuits. Thus, our results form the basis for future studies that will test the potential of microRNA manipulation as novel therapeutic option for diseases that are charcterized by impaired neuronal homeostasis.