miR-128 as a Regulator of Synaptic Properties in 5xFAD Mice Hippocampal Neurons

Shvarts-Serebro, Inna; Sheinin, Anton; Gottfried, Irit; Adler, Lior; Schottlender, Nofar; Ashery, Uri; Barak, Boaz

doi:10.1007/s12031-021-01862-2

Cited by 9 publications

(9 citation statements)

References 98 publications

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“…To this end, knocking out miR-128 in 3xTg-AD mice, a widely used mouse model of AD [ 63 ], improved cognitive deficits and reduced Aβ pathology [ 58 ]. Similar results were obtained using a different mouse model of AD [ 64 ]. Despite these findings, the mechanism by which miR-128 is linked to AD remains unknown.…”

Section: Mir-128 In Neurodegenerative Diseasesupporting

confidence: 86%

The Role of miR-128 in Neurodegenerative Diseases

Lanza

Cuzzocrea

Oddo

et al. 2023

IJMS

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Several neurodegenerative disorders are characterized by the accumulation of misfolded proteins and are collectively known as proteinopathies. Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) represent some of the most common neurodegenerative disorders whose steady increase in prevalence is having a major socio-economic impact on our society. Multiple laboratories have reported hundreds of changes in gene expression in selective brain regions of AD, PD, and HD brains. While the mechanisms underlying these changes remain an active area of investigation, alterations in the expression of noncoding RNAs, which are common in AD, PD, and HD, may account for some of the changes in gene expression in proteinopathies. In this review, we discuss the role of miR-128, which is highly expressed in mammalian brains, in AD, PD, and HD. We highlight how alterations in miR-128 may account, at least in part, for the gene expression changes associated with proteinopathies. Indeed, miR-128 is involved, among other things, in the regulation of neuronal plasticity, cytoskeletal organization, and neuronal death, events linked to various proteinopathies. For example, reducing the expression of miR-128 in a mouse model of AD ameliorates cognitive deficits and reduces neuropathology. Overall, the data in the literature suggest that targeting miR-128 might be beneficial to mitigate the behavioral phenotype associated with these diseases.

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Section: Mir-128 In Neurodegenerative Diseasesupporting

confidence: 86%

The Role of miR-128 in Neurodegenerative Diseases

Lanza

Cuzzocrea

Oddo

et al. 2023

IJMS

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“…The dramatic transcriptional alterations in multiple mRNAs related to specific myelination and cell differentiation pathways in NexKO mice [ 56 ] have led us to explore whether there are master regulators that mediate these changes. The myriad of data supporting the involvement of microRNAs (miRNAs or miRs) in the development of the nervous system [ 60 , 61 , 62 , 63 , 64 , 65 , 66 ] encouraged us to explore miRNAs in the context of the neurodevelopmental deficits found in NexKO mice compared to controls. miRNAs are small (~22 nucleotides), endogenous, non-coding RNA molecules that downregulate mRNA expression post-transcriptionally, thus leading to a reduced expression of their protein products [ 60 , 67 ].…”

Section: Introductionmentioning

confidence: 99%

Altered White Matter and microRNA Expression in a Murine Model Related to Williams Syndrome Suggests That miR-34b/c Affects Brain Development via Ptpru and Dcx Modulation

Grad

Nir

Levy

et al. 2022

Cells

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Williams syndrome (WS) is a multisystem neurodevelopmental disorder caused by a de novo hemizygous deletion of ~26 genes from chromosome 7q11.23, among them the general transcription factor II-I (GTF2I). By studying a novel murine model for the hypersociability phenotype associated with WS, we previously revealed surprising aberrations in myelination and cell differentiation properties in the cortices of mutant mice compared to controls. These mutant mice had selective deletion of Gtf2i in the excitatory neurons of the forebrain. Here, we applied diffusion magnetic resonance imaging and fiber tracking, which showed a reduction in the number of streamlines in limbic outputs such as the fimbria/fornix fibers and the stria terminalis, as well as the corpus callosum of these mutant mice compared to controls. Furthermore, we utilized next-generation sequencing (NGS) analysis of cortical small RNAs’ expression (RNA-Seq) levels to identify altered expression of microRNAs (miRNAs), including two from the miR-34 cluster, known to be involved in prominent processes in the developing nervous system. Luciferase reporter assay confirmed the direct binding of miR-34c-5p to the 3’UTR of PTPRU—a gene involved in neural development that was elevated in the cortices of mutant mice relative to controls. Moreover, we found an age-dependent variation in the expression levels of doublecortin (Dcx)—a verified miR-34 target. Thus, we demonstrate the substantial effect a single gene deletion can exert on miRNA regulation and brain structure, and advance our understanding and, hopefully, treatment of WS.

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“…In agreement with our observation of reduced miR-128-3p expression upon circRERE knockdown, miR-128-3p deficiency in D1 dopaminergic neurons results in increased dendritic spine number (Tan et al, 2013). However, miR-128-3p deficiency was further shown to lead to increased neuronal excitability in multiple studies, which culminates in an increased susceptibility for epileptic seizures (Tan et al ., 2013) (Franzoni et al, 2015) (Rehfeld et al ., 2018) (McSweeney et al, 2016) (Shvarts-Serebro et al, 2021) . This would suggest that the effects of circRERE on synapse formation and function are uncoupled and display differential dependency with regards to miR-128-3p.…”

Section: Discussionmentioning

confidence: 99%

A functional screen uncovers circular RNAs regulating excitatory synaptogenesis in hippocampal neurons

Kelly,

Bicker,

Winterer

et al. 2024

Preprint

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Circular RNAs (circRNAs) are an expanding class of largely unexplored RNAs which are prominently enriched in the mammalian brain. Here, we systematically interrogated their role in excitatory synaptogenesis of rat hippocampal neurons using RNA interference. Thereby, we identified seven circRNAs as negative regulators of excitatory synapse formation, many of which contain high-affinity microRNA binding sites. Knockdown of one of these candidates, circRERE, surprisingly promoted the formation of electrophysiologically silent synapses. Mechanistically, circRERE knockdown resulted in a preferential upregulation of synaptic mRNAs containing binding sites for miR-128-3p because of a reduced protective interaction between miR-128-3p and circRERE. Accordingly, overexpression of circRERE rescued exaggerated synapse formation upon circRERE knockdown in a miR-128-3p binding site-specific manner. Overall, our results uncover circRERE-mediated stabilization of miR-128-3p as a novel mechanism to restrict the formation of silent excitatory synaptic co-clusters and more generally implicate circRNA-dependent microRNA regulation in the control of synapse development and function.

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miR-128 as a Regulator of Synaptic Properties in 5xFAD Mice Hippocampal Neurons

Cited by 9 publications

References 98 publications

The Role of miR-128 in Neurodegenerative Diseases

The Role of miR-128 in Neurodegenerative Diseases

Altered White Matter and microRNA Expression in a Murine Model Related to Williams Syndrome Suggests That miR-34b/c Affects Brain Development via Ptpru and Dcx Modulation

A functional screen uncovers circular RNAs regulating excitatory synaptogenesis in hippocampal neurons

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