Multimodal profiling of single-cell morphology, electrophysiology, and gene expression using Patch-seq
Open accessAbstract
Neurons exhibit a rich diversity of morphological phenotypes, electrophysiological properties, and gene-expression patterns. Understanding how these different characteristics are interrelated at the single-cell level has been difficult because of the lack of techniques for multimodal profiling of individual cells. We recently developed Patch-seq, a technique that combines whole-cell patch-clamp recording, immunohistochemistry, and single-cell RNA-sequencing (scRNA-seq) to comprehensively profile single neurons from mouse brain slices. Here, we present a detailed step-by-step protocol, including modifications to the patching mechanics and recording procedure, reagents and recipes, procedures for immunohistochemistry, and other tips to assist researchers in obtaining high-quality morphological, electrophysiological, and transcriptomic data from single neurons. Successful implementation of Patch-seq allows researchers to explore the multidimensional phenotypic variability among neurons and to correlate gene expression with phenotype at the level of single cells. The entire procedure can be completed in ∼2 weeks through the combined efforts of a skilled electrophysiologist, molecular biologist, and biostatistician.
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The study used Patch-seq to describe the morpho-electric phenotypes for most of the t-types in MOp.
“We used the Patch-seq technique8,17–19 to describe the morpho-electric phenotypes for most of the t-types in MOp20.”
From Phenotypic variation of transcriptomic cell types in mouse motor cortex (2021) · cites this paper as [17]
The RNA extraction process may have interfered with biocytin diffusion and MOp is quite thick, making it difficult to recover complete morphologies of some groups of neurons, such as deep L5 Martinotti cells.
“Second, as the RNA extraction process may have interfered with biocytin diffusion17 and as MOp is quite thick, it was difficult to recover complete morphologies of some groups of neurons, such as deep L5 Martinotti cells with thin long axons that reach all the way to L1.”
From Phenotypic variation of transcriptomic cell types in mouse motor cortex (2021) · cites this paper as [17]
The addition of the RNase inhibitor resulted in an increase in osmolarity to the desired value of 315-320 mOSM without a further dilution.
“The addition of the inhibitor resulted in an increase in osmolarity to the desired value of 315–320 mOSM without a further dilution17.”
From Phenotypic variation of transcriptomic cell types in mouse motor cortex (2021) · cites this paper as [17]
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Research works printed but not linked: 3
- Cadwell CR & Tolias AS (2016) Correlating cellular morphology, physiology, and gene expression using Patch-Seq. In: Using single-cell genomics to analyze neurons, glia, and circuits. (McCarroll S, ed) pp. 41– 51. San Diego, CA: Society for Neuroscience.
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- Authors
- Cadwell, C. R., Scala, F., Li, S., Livrizzi, G., Shen, S., Sandberg, R., Jiang, X., & Tolias, A. S.
- Affiliations
- Baylor College of Medicine (US)
- Karolinska Institutet (SE)
- Corresponding author
- Sandberg, Rickard
- Jiang, Xiaolong
- Tolias, Andreas S
- ORCID
- Venue
- Nature Protocols
- Published
- 2017-11-16
- Volume
- 12
- Issue
- 12
- Pages
- 2531-2553
- ISSN
- 1750-2799 (ISSN-L)
- 1754-2189
- PMC
- PMC6422019
- OpenAlex
- W2769765726
- Cited by
- 147
- References
- 40
- Citations by year
- 2026: 5 · 2025: 14 · 2024: 25 · 2023: 19 · 2022: 22 · 2021: 19 · 2020: 22 · 2019: 10 · 2018: 11
- FWCI
- 4.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Protocols (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (1dp1od008301-01)
- National Institute of Mental Health (F30MH095440, R01MH103108)
- National Eye Institute (DP1EY023176, P30EY002520, T32EY007001)
- National Institute of General Medical Sciences (T32GM007330)
- National Institute of Biomedical Imaging and Bioengineering (T32EB006350)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neural Engineering
- Keywords
- Patch-seq, single neurons, neuronal morphology, neuronal electrophysiology, single-cell transcriptomics, whole-cell patch-clamp recording, immunohistochemistry, mouse brain slices
- MeSH terms
- Animals, Cells, Cultured, Immunohistochemistry, Neurons, Sequence Analysis, RNA, Patch-Clamp Techniques, Gene Expression Profiling, Mice, Electrophysiological Phenomena, Single-Cell Analysis, Transcriptome
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