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The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity, and memory deficits in Down syndrome

Molecular Psychiatry (2024)Cite this article

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Abstract

Down syndrome (DS) stands as the prevalent genetic cause of intellectual disability, yet comprehensive understanding of its cellular and molecular underpinnings remains limited. In this study, we explore the cellular landscape of the hippocampus in a DS mouse model, the Ts65Dn, through single-nuclei transcriptional profiling. Our findings demonstrate that trisomy manifests as a highly specific modification of the transcriptome within distinct cell types. Remarkably, we observed a significant shift in the transcriptomic profile of granule cells in the dentate gyrus (DG) associated with trisomy. We identified the downregulation of a specific small nucleolar RNA host gene, Snhg11, as the primary driver behind this observed shift in the trisomic DG. Notably, reduced levels of Snhg11 in this region were also observed in a distinct DS mouse model, the Dp(16)1Yey, as well as in human postmortem brain tissue, indicating its relevance in Down syndrome. To elucidate the function of this long non-coding RNA (lncRNA), we knocked down Snhg11 in the DG of wild-type mice. Intriguingly, this intervention alone was sufficient to impair synaptic plasticity and adult neurogenesis, resembling the cognitive phenotypes associated with trisomy in the hippocampus. Our study uncovers the functional role of Snhg11 in the DG and underscores the significance of this lncRNA in intellectual disability. Furthermore, our findings highlight the importance of DG in the memory deficits observed in Down syndrome.

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Fig. 1: Unbiased identification of neuronal subtypes in hippocampus.
Fig. 2: Differentially expressed genes (DEGs) in the trisomic hippocampal cell types.
Fig. 3: Transcriptomic shift specific to the dentate gyrus.
Fig. 4: Snhg11 knockdown in the WT Dentate gyrus leads to transcriptomic alterations similar to those of TS mice.
Fig. 5: Snhg11 knockdown in the WT dentate gyrus leads to deficits in neurogenesis and long-term potentiation.
Fig. 6: Snhg11 knockdown effects on hippocampal-dependent memory in WT, WT injected either with control-ASO or Snhg11-ASO and TS mice.

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Data availability

The snRNA-seq and bulk RNA-seq data that support the findings of this study have been deposited in the Gene Expression Omnibus repository, with the series records GSE212351 and GSE212258. Basecalled FAST5 of nanopore direct RNA sequencing runs have been deposited to ENA, under accession code PRJEB58921. All the processed data and supplementary materials are available upon request.

Code availability

The software used in this study is available at the following online repositories. R package Seurat version 2.3.4: https://github.com/satijalab/seurat; R package Destiny version 1.1.0: https://github.com/theislab/destiny; R package DESeq2 version 1.34.0: https://bioconductor.org/packages/release/bioc/html/DESeq2.html; R package Rsubread version 2.12.3: https://bioconductor.org/packages/release/bioc/html/Rsubread.html; R package BioMart version 2.54.1: https://bioconductor.org/packages/release/bioc/html/biomaRt.html; plots were made with ggplot2: https://cloud.r-project.org/web/packages/ggplot2/index.html. R version 4.2.1. Custom codes used in this study are available upon request.

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Acknowledgements

We thank the Single Cell Genomics Team at the National Center for Genomic Analysis (CNAG) led by Holger Heyn for their assistance with experiment planning and sequencing and for the fruitful discussion throughout this project. We are grateful to the CRG Genomics Unit for the support and assistance in this work. We thank Marie-Claude Potier lab for providing and dissecting the Dp16 DG tissues. Human tissue was obtained from the Biobank of the Hospital Clinic of Barcelona. We acknowledge the support of the Spanish Ministry of Science and Innovation through the Centro de Excelencia Severo Ochoa (CEX2020‐001049‐S, MCIN/AEI /10.13039/501100011033), the Generalitat de Catalunya through the CERCA program and to the EMBL partnership. We are grateful to the CRG Core Technologies Program for their support and assistance in this work.

Funding

The lab of MD is recognized by the Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement de la Generalitat de Catalunya (Grups consolidats 2023). This project has received funding from the Agencia Estatal de Investigación (PID2019-110755RB-I00/AEI/10.13039/501100011033; PID2022-141900OB-I00 INTO-DS), from the European Union’s Horizon 2020 research and innovation program under grant agreement No 848077 and 899986, Jerôme Lejeune Foundation #2002, Fundació La Marató-TV3 (#2016/20-30), Ministerio de Ciencia Innovación y Universidades (RTC2019-007230-1, RTC2019-007329-1; and CPP2022-009659). The CIBER of Rare Diseases is an initiative of the ISCIII. C.S. received the FI grant from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) de la Generalitat de Catalunya, M.S.N. received an FPU fellowship (FPU19/04789) from Ministerio de Universidades and A.F.B. received an FPI-SO fellowship (PRE2018-084504). S.C. is supported by “la Caixa” InPhINIT Ph.D. fellowship (LCF/BQ/DI19/11730036). The lab of EMN is funded by the Spanish Ministry of Economy, Industry and Competitiveness (PID2021-128193NB-100 to EMN) and the European Research Council (ERC-2021-STG no. 101042103 to EMN).

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Authors and Affiliations

  1. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, Barcelona, 08003, Spain

    Cesar Sierra, Miguel Sabariego-Navarro, Álvaro Fernández-Blanco, Sonia Cruciani, Alfonsa Zamora-Moratalla & Eva Maria Novoa

  2. Universitat Pompeu Fabra (UPF), Dr Aiguader 88, Barcelona, 08003, Spain

    Miguel Sabariego-Navarro, Sonia Cruciani, Eva Maria Novoa & Mara Dierssen

  3. Biomedical Research Networking Center for Rare Diseases (CIBERER), Barcelona, Spain

    Mara Dierssen

Authors
  1. Cesar Sierra
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  2. Miguel Sabariego-Navarro
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  3. Álvaro Fernández-Blanco
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  4. Sonia Cruciani
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  5. Alfonsa Zamora-Moratalla
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  6. Eva Maria Novoa
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  7. Mara Dierssen
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Contributions

MD and CS conceived, designed and coordinated the study, and wrote the manuscript. CS collected and analyzed sequencing datasets. CS and AFB conducted in vivo animal experiments and CS in vitro experiments. MSN and AZM conducted the electrophysiology experiments. SC performed the Nanopore sequencing experiments and their analyses, under the supervision of EMN. All authors revised and corrected the final version of the manuscript.

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Correspondence to Cesar Sierra or Mara Dierssen.

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Sierra, C., Sabariego-Navarro, M., Fernández-Blanco, Á. et al. The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity, and memory deficits in Down syndrome. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02440-9

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