Nanoscale imaging reveals miRNA-mediated control of functional states of dendritic spines

Abstract

Dendritic spines are major loci of excitatory inputs and undergo activity-dependent structural changes that contribute to synaptic plasticity and memory formation. Despite the existence of various classification types of spines, how they arise and which molecular components trigger their structural plasticity remain elusive. microRNAs (miRNAs) have emerged as critical regulators of synapse development and plasticity via their control of gene expression. Brain-specific miR-134s likely regulate the morphological maturation of spines, but their subcellular distributions and functional impacts have rarely been assessed. Here, we exploited atomic force microscopy to visualize in situ miR-134s, which indicated that they are mainly distributed at nearby dendritic shafts and necks of spines. The abundance of miR-134s varied between morphologically and functionally distinct spine types, and their amounts were inversely correlated with their postulated maturation stages. Moreover, spines exhibited reduced contents of miR-134s when selectively stimulated with beads containing brain-derived neurotropic factor (BDNF). Taken together, in situ visualizations of miRNAs provided unprecedented insights into the “inverse synaptic-tagging” roles of miR-134s that are selective to inactive/irrelevant synapses and potentially a molecular means for modifying synaptic connectivity via structural alteration.

microRNAs as Early Biomarkers of Alzheimer’s Disease: A Synaptic Perspective

“…Increasing evidence indicates that the alteration of protein functionality in the synapse could be involved in early synaptic alterations in AD [ 26 , 27 ]. Given the regulatory role of miRNAs, those miRNAs targeting synaptic-related proteins may be an important mechanism underlying the synaptic dysfunction present in early stages of the disease [ 49 ]. Thus, alterations in the levels of specific miRNAs could be important in the development of synaptic pathology that leads to neurodegeneration in AD by modifying the synaptic structure and function that underlie synaptic plasticity.…”

“…On the other hand, miR-134 can also facilitate homeostatic synaptic depression in response to chronic activity, targeting the local translational repressor Pumilio-2 [ 66 ]. Recently, miR-134 localization in dendrites has been supported using atomic force microscopy showing a negative correlation between the amount of miRNA and the maturity and function of synapses [ 49 ]. Other members of the family, miR-132 and miR-138, were also linked to synaptic formation and function [ 63 ].…”

miRNA-Dependent Control of Homeostatic Plasticity in Neurons

“…In support of a role for miRNAs in regulating the function of local compartments like synapses, subcellular fractionation and in situ hybridization experiments revealed that several miRNAs are present in dendrites, axons or even synapses and that neuronal activity regulates both their abundance and function (Kye et al, 2007; Lugli et al, 2008; Schratt, 2009; Siegel et al, 2009; Natera-Naranjo et al, 2010). Interestingly, the distribution of miRNAs seems to parallel the distribution of their cognate target mRNAs (Kye et al, 2007); such a spatial proximity may enable the efficient regulation of local protein translation to serve a specific function at the right time and place (Kosik, 2016; Park et al, 2019).…”

“…Using a fluorescent pre-miRNA sensor to probe Dicer activity, it was recently shown that the local stimulation of single spines through glutamate uncaging promotes the maturation of miR-181a in a NMDAR-dependent manner, leading to the local repression of CamKIIα synthesis (Sambandan et al, 2017). Furthermore, the local abundance of miR-134, previously implicated in PTX-induced downscaling (Fiore et al, 2014), varies depending on spine maturation and activity, while BDNF local stimulation leads to a decrease in the number of miR-134 copies present at the neck of spines (Park et al, 2019). In addition to the local control of miRNA maturation through Dicer, neuronal activity regulate the turnover of the RISC complex itself, which could possibly impact miR-dependent local protein translation in a non-specific way.…”

Targeting microRNA-134 for seizure control and disease modification in epilepsy

“…In recent work, Park and colleagues used atomic force microscopy to estimate the copy number of miR-134 at synapses. They found that immature synapses typically had 10–15 molecules, mainly found at the base of the spine [31]. In contrast, numbers of miR-134 molecules were about half that at mature synapses.…”