miR-329 and miR-495-mediated Prr7 downregulation is required for homeostatic synaptic depression in rat hippocampal neurons

Inouye, Michiko O.; Colameo, David; Ammann, Irina; Schratt, Gerhard

doi:10.1101/2022.03.08.483397

Cited by 4 publications

(1 citation statement)

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“…It has been reported that miR-329-3p and miR-495-3p induce homeostatic synaptic depression (HSD) and inhibit chronic increases in network activity. These miRNAs inhibit proline-rich protein 7/ transmembrane adapter protein 3 (Prr7) which is the protein involved in the stability of excitatory synapses and the size of dendritic spines at the synaptic site through protection of synaptic proteins (Inouye et al, 2022).…”

Section: Micrornas Are Important Regulators Of Neural Development In ...mentioning

confidence: 99%

The role of microRNAs in neurobiology and pathophysiology of the hippocampus

Rashidi,

Kalirad,

Rafie

et al. 2023

Front. Mol. Neurosci.

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MicroRNAs (miRNAs) are short non-coding and well-conserved RNAs that are linked to many aspects of development and disorders. MicroRNAs control the expression of genes related to different biological processes and play a prominent role in the harmonious expression of many genes. During neural development of the central nervous system, miRNAs are regulated in time and space. In the mature brain, the dynamic expression of miRNAs continues, highlighting their functional importance in neurons. The hippocampus, as one of the crucial brain structures, is a key component of major functional connections in brain. Gene expression abnormalities in the hippocampus lead to disturbance in neurogenesis, neural maturation and synaptic formation. These disturbances are at the root of several neurological disorders and behavioral deficits, including Alzheimer’s disease, epilepsy and schizophrenia. There is strong evidence that abnormalities in miRNAs are contributed in neurodegenerative mechanisms in the hippocampus through imbalanced activity of ion channels, neuronal excitability, synaptic plasticity and neuronal apoptosis. Some miRNAs affect oxidative stress, inflammation, neural differentiation, migration and neurogenesis in the hippocampus. Furthermore, major signaling cascades in neurodegeneration, such as NF-Kβ signaling, PI3/Akt signaling and Notch pathway, are closely modulated by miRNAs. These observations, suggest that microRNAs are significant regulators in the complicated network of gene regulation in the hippocampus. In the current review, we focus on the miRNA functional role in the progression of normal development and neurogenesis of the hippocampus. We also consider how miRNAs in the hippocampus are crucial for gene expression mechanisms in pathophysiological pathways.

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Section: Micrornas Are Important Regulators Of Neural Development In ...mentioning

confidence: 99%

The role of microRNAs in neurobiology and pathophysiology of the hippocampus

Rashidi,

Kalirad,

Rafie

et al. 2023

Front. Mol. Neurosci.

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Involvement of extracellular vesicle microRNA clusters in developing healthy and Rett syndrome brain organoids

Bahram Sangani,

Koetsier,

Gomes

et al. 2024

Cell. Mol. Life Sci.

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Rett syndrome (RTT) is a neurodevelopmental disorder caused by de novo mutations in the MECP2 gene. Although miRNAs in extracellular vesicles (EVs) have been suggested to play an essential role in several neurological conditions, no prior study has utilized brain organoids to profile EV-derived miRNAs during normal and RTT-affected neuronal development. Here we report the spatiotemporal expression pattern of EV-derived miRNAs in region-specific forebrain organoids generated from female hiPSCs with a MeCP2:R255X mutation and the corresponding isogenic control. EV miRNA and protein expression profiles were characterized at day 0, day 13, day 40, and day 75. Several members of the hsa-miR-302/367 cluster were identified as having a time-dependent expression profile with RTT-specific alterations at the latest developmental stage. Moreover, the miRNA species of the chromosome 14 miRNA cluster (C14MC) exhibited strong upregulation in RTT forebrain organoids irrespective of their spatiotemporal location. Together, our results suggest essential roles of the C14MC and hsa-miR-302/367 clusters in EVs during normal and RTT-associated neurodevelopment, displaying promising prospects as biomarkers for monitoring RTT progression. Graphical Abstract

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microRNA-218-5p Coordinates Scaling of Excitatory and Inhibitory Synapses during Homeostatic Synaptic Plasticity

Colameo,

Maley,

ElGrawani

et al. 2023

Preprint

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Homeostatic synaptic plasticity (HSP) is a fundamental neuronal mechanism that allows networks to compensate for prolonged changes in activity by adjusting synaptic strength. This process is crucial for maintaining stable brain function and has been implicated in memory consolidation during sleep. While scaling of both excitatory and inhibitory synapses plays an important role during homeostatic synaptic plasticity, molecules coordinating both of these processes are unknown. In this study, we investigate the role of miR-218-5p as a regulator of inhibitory and excitatory synapses in the context of picrotoxin (PTX)-induced homeostatic synaptic downscaling (HSD) in rat hippocampal neurons. Using enrichment analysis of miRNA-binding sites in differentially expressed genes changing upon PTX-induced HSD, we bioinformatically predicted and experimentally validated increased miR-218-5p activity upon PTX-treatment in the process compartment. By monitoring synapse structure in vitro with confocal microscopy, we demonstrate that inhibiting miR-218-5p activity exerts a dual effect during HSD: it prevents the downscaling of excitatory synapses and dendritic spines, while at the same time blocking inhibitory synapse upscaling. Furthermore, we identify the Neuroligin2 interacting molecule Mdga1 as a crucial target of miR-218-5p in the context of homeostatic upscaling of inhibitory synapses. By performing long-term electroencephalographic (EEG) recordings, we further revealed that local inhibition of miR-218-5p in the somatosensory cortex reduced local slow-wave activity (SWA) during non-rapid-eye-movement (NREM) sleep. In summary, this study uncovers miR-218-5p as a key player in coordinating inhibitory and excitatory synapses during homeostatic plasticity and sleep. Our findings contribute to a deeper understanding of how neural circuits maintain stability in the face of activity-induced perturbations, with potential implications for both physiological and pathological conditions.

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miR-329 and miR-495-mediated Prr7 downregulation is required for homeostatic synaptic depression in rat hippocampal neurons

Cited by 4 publications

References 58 publications

The role of microRNAs in neurobiology and pathophysiology of the hippocampus

The role of microRNAs in neurobiology and pathophysiology of the hippocampus

Involvement of extracellular vesicle microRNA clusters in developing healthy and Rett syndrome brain organoids

microRNA-218-5p Coordinates Scaling of Excitatory and Inhibitory Synapses during Homeostatic Synaptic Plasticity

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