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From high-throughput transcriptome characterization of individual synaptosomes to constructing the whole-brain connectome

Neuropsychopharmacology volume 49, pages 325–326 (2024)Cite this article

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From the synaptome of the mouse hippocampus, we identified 12 synapse-associated clusters potentially corresponding to various synaptic states and subcellular structures such as neuron-astrocyte junctions, neuron-oligodendrocyte junctions, and axon initial segments [2]. By comparing the synaptome to the matched single-nucleus transcriptome, we readily identified the neuron compartment-dependent RNA expression preferences. The effective intron detection warranted by the total-RNA approach allows the characterization of synaptic splicing landscapes. We observed that transcripts responsible for synaptogenesis tend to be transported in unspliced forms. Next, we characterized the synaptic pathology (synaptopathy) in an Alzheimer’s Disease mouse model 5xFAD. We characterized gene expression changes associated with synaptopathy. As a result, we pinned down the most vulnerable pathways to the synapses, such as the complement-mediated synaptic pruning [3]. We also demonstrated that synaptome profiling could be applied to postmortem human brain tissues. Characterization of synaptopathy of various neurological and psychiatric diseases is greatly desired, which we believe will shed new light on the etiology of the diseases and unveil new therapeutic targets for treatment.

Beyond profiling gene expression in synapses, synaptome profiling could provide an alternative approach to map neural connectivity (“connectome”) using high-throughput next-generation sequencing platforms. This sequencing-based connectome mapping method requires the introduction of a neuron-unique barcode using viruses with no trans-synaptic crossing, similar to the MAPseq/BARseq [4]. The neuron-neuron connections can be identified through the simultaneous detection of two neuron-specific barcodes in the synaptosomes in a high-throughput manner (Fig. 1B). Meanwhile, the neuron identity (both barcode and neuron type) could be retrieved from the single-nucleus transcriptome of the same sample (Fig. 1B). Considering the scale of 108 neurons and at least 1012 synapses in a single mouse brain, we reason that the major technical challenge is a reasonable sampling of this ultra-large number of neurons and connectivity. Integration of split-and-pool strategy [5] could potentially boost the throughput of MATQ-Drop to the order of billions, thereby enabling the connectome construction at the whole-brain level.

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Fig. 1: Scheme of synaptome profiling and connectome construction.

References

  1. Ahmadi A, Gispert JD, Navarro A, Vilor-Tejedor N, Sadeghi I. Single-cell transcriptional changes in neurodegenerative diseases. Neuroscience. 2021;479:192–205. https://doi.org/10.1016/j.neuroscience.2021.10.025.

    Article  CAS  PubMed  Google Scholar 

  2. Niu M, Cao W, Wang Y, Zhu Q, Luo J, Wang B, et al. Droplet-based transcriptome profiling of individual synapses. Nat Biotechnol. 2023. https://doi.org/10.1038/s41587-022-01635-1.

  3. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6. https://doi.org/10.1126/science.aad8373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chen Y, Chen X, Baserdem B, Zhan H, Li Y, Davis MB, et al. High-throughput sequencing of single neuron projections reveals spatial organization in the olfactory cortex. Cell. 2022;185:4117–34.e28. https://doi.org/10.1016/j.cell.2022.09.038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Rosenberg AB, Roco CM, Muscat RA, Kuchina A, Sample P, Yao Z, et al. Single-cell profiling of the developing mouse brain and spinal cord with split-pool barcoding. Science. 2018;360:176–82. https://doi.org/10.1126/science.aam8999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Citri A, Malenka RC. Synaptic plasticity: multiple forms, functions, and mechanisms. Neuropsychopharmacology. 2008;33:18–41. https://doi.org/10.1038/sj.npp.1301559.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to the McNair family for the support through McNair Scholarship.

Funding

CZ is supported by McNair Scholarship, NIH Director’s New Innovator Award (1DP2EB020399), NSF Behavioral Plasticity Research Institute (BPRI) (DBI-2021795), and NIH SMaHT Program (1UG3NS132132 & 1UM1DA058229-01).

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Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Muchun Niu & Chenghang Zong

  2. Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Muchun Niu

  3. Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Chenghang Zong

  4. McNair Medical Institute, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Chenghang Zong

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MN and CZ wrote the manuscript.

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Correspondence to Chenghang Zong.

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MN and CZ are co-founders and equity holders of Pioneer Genomics Inc.

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Niu, M., Zong, C. From high-throughput transcriptome characterization of individual synaptosomes to constructing the whole-brain connectome. Neuropsychopharmacol. 49, 325–326 (2024). https://doi.org/10.1038/s41386-023-01697-y

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