MicroRNA-138 controls hippocampal interneuron function and short-term memory in mice

Daswani, Reetu; Gilardi, Carlotta; Soutschek, Michael; Nanda, Prakruti; Weiß, Kerstin; Bicker, Silvia; Fiore, R.; Dieterich, Christoph; Germain, Pierre-Luc; Winterer, Jochen; Schratt, Gerhard

doi:10.7554/elife.74056

Cited by 22 publications

(13 citation statements)

References 57 publications

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“…[ 59 ]), where it is thought to promote the early stages of oligodendrocyte differentiation while preventing their final maturation, thereby facilitating the correct selection of axons and appropriate myelination [ 59 ]. No staining was detectable among GFAP-stained astrocytes in agreement with observations in the brain by Daswani and cols [ 57 ].…”

Section: Discussionsupporting

confidence: 91%

“…A similar distribution is observed in the spinal cord of mice ( Mus musculus C57BL/6J strain) according to ongoing studies from the lab (see Uceta [ 56 ]). In fact, regionalization of neuronal expression of miR-138-5p is also observed in the brain [ 46 , 55 , 57 ] and seems common among microRNAs (see, for example, miR-34 expression in spine neurons in Chang and cols. [ 58 ]).…”

Section: Discussionmentioning

confidence: 99%

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MicroRNA-138-5p Targets Pro-Apoptotic Factors and Favors Neural Cell Survival: Analysis in the Injured Spinal Cord

et al. 2022

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The central nervous system microRNA miR-138-5p has attracted much attention in cancer research because it inhibits pro-apoptotic genes including CASP3. We hypothesize that miR-138-5p downregulation after SCI leads to overexpression of pro-apoptotic genes, sensitizing neural cells to noxious stimuli. This study aimed to identify miR-138-5p targets among pro-apoptotic genes overexpressed following SCI and to confirm that miR-138-5p modulates cell death in neural cells. Gene expression and histological analyses revealed that the drop in miR-138-5p expression after SCI is due to the massive loss of neurons and oligodendrocytes and its downregulation in neurons. Computational analyses identified 176 potential targets of miR-138-5p becoming dysregulated after SCI, including apoptotic proteins CASP-3 and CASP-7, and BAK. Reporter, RT-qPCR, and immunoblot assays in neural cell cultures confirmed that miR-138-5p targets their 3′UTRs, reduces their expression and the enzymatic activity of CASP-3 and CASP-7, and protects cells from apoptotic stimuli. Subsequent RT-qPCR and histological analyses in a rat model of SCI revealed that miR-138-5p downregulation correlates with the overexpression of its pro-apoptotic targets. Our results suggest that the downregulation of miR-138-5p after SCI may have deleterious effects on neural cells, particularly on spinal neurons.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

MicroRNA-138-5p Targets Pro-Apoptotic Factors and Favors Neural Cell Survival: Analysis in the Injured Spinal Cord

et al. 2022

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“…Hippocampal slices from male animals derived from the genetic deletion (WT vs cKO), AAV deletion and Myl9/Mustn1 overexpression cohorts (300 μm thick) were prepared at 4 °C, as previously described [46]…”

Section: Electrophysiologymentioning

confidence: 99%

miRNA-mediated inhibition of an actomyosin network in hippocampal pyramidal neurons restricts sociability in adult male mice

Narayanan,

Levone,

Winterer

et al. 2023

Preprint

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Social deficits are frequently observed in patients suffering from neurodevelopmental disorders, but the molecular mechanisms regulating sociability are still poorly understood. We recently reported that the loss of the microRNA cluster miR-379-410 leads to hypersocial behavior and anxiety in mice. Here, we show that ablating miR-379-410 in excitatory neurons of the postnatal mouse hippocampus recapitulates hypersociability, but not anxiety. At the cellular level, miR-379-410 loss in excitatory neurons leads to increased excitatory synaptic transmission and upregulation of an actomyosin gene network. Re-expression of three cluster miRNAs, as well as pharmacological inhibition of the actomyosin activator ROCK, was sufficient to reinstate normal sociability in miR-379-410 knockout mice. Several actomyosin genes and miR-379-410 family members were reciprocally dysregulated in isogenic human iPSC-derived neurons harboring a deletion present in Williams-Beuren-Syndrome patients, which are characterized by hypersocial behavior. Together, our results unveil a novel microRNA-actomyosin pathway involved in the control of sociability.

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“…In cortical structures most of the work has focused on PNs. However, recent research has demonstrated crucial roles for miRNAs in INs, from early development (survival, specification, and lamination of medial ganglionic eminence-derived INs) to cognitive functions and memory formation (Daswani et al, 2022; Qiu et al, 2020; Tuncdemir et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-218 instructs proper assembly of hippocampal networks

Taylor

Kobayashi

Vilella

et al. 2022

Preprint

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The assembly of the mammalian brain is orchestrated by temporally coordinated waves of gene expression. A key aspect of this developmental program is mediated at the post-transcriptional level by microRNAs (miRNAs). Deletion of neuronal enriched miRNAs induces strong developmental phenotypes, and multiple reports have found altered levels of miRNAs in patients with neurodevelopmental disorders. However, cellular and molecular mechanisms used by miRNAs to instruct proper brain development remain largely unexplored. Here, through multiple screens, we identified miR-218 as a critical regulator of hippocampal assembly in mice. MiR-218 is highly expressed in the hippocampus and enriched in both excitatory principal neurons and GABAergic inhibitory interneurons. Transient inhibition of miR-218 in early life results in an adult brain with heightened network activity and a predisposition to seizures. We used RNA-seq and FACS-seq (fluorescence-activated cell sorting followed by RNA-seq) to identify global and cell type-specific changes in gene expression in the absence of miR-218 and narrow down which altered developmental processes would lead to long-term network instability. We find that miR-218 inhibition results in the disruption of early depolarizing GABAergic signaling, structural defects in dendritic spines, and altered intrinsic membrane excitability. Finally, conditional knockout of miR-218 in interneurons, but not pyramidal neurons is sufficient to recapitulate the effects on long-term stability. Taken together, the data suggest that miR-218 orchestrates hippocampal network assembly to produce a stable network in the adult, primarily by regulating interneuron function in early postnatal life.

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MicroRNA-138 controls hippocampal interneuron function and short-term memory in mice

Cited by 22 publications

References 57 publications

MicroRNA-138-5p Targets Pro-Apoptotic Factors and Favors Neural Cell Survival: Analysis in the Injured Spinal Cord

MicroRNA-138-5p Targets Pro-Apoptotic Factors and Favors Neural Cell Survival: Analysis in the Injured Spinal Cord

miRNA-mediated inhibition of an actomyosin network in hippocampal pyramidal neurons restricts sociability in adult male mice

MicroRNA-218 instructs proper assembly of hippocampal networks

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