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Gene expression changes following chronic antipsychotic exposure in single cells from mouse striatum

Molecular Psychiatry volume 27, pages 2803–2812 (2022)Cite this article

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Abstract

Schizophrenia is an idiopathic psychiatric disorder with a high degree of polygenicity. Evidence from genetics, single-cell transcriptomics, and pharmacological studies suggest an important, but untested, overlap between genes involved in the etiology of schizophrenia and the cellular mechanisms of action of antipsychotics. To directly compare genes with antipsychotic-induced differential expression to genes involved in schizophrenia, we applied single-cell RNA-sequencing to striatal samples from male C57BL/6 J mice chronically exposed to a typical antipsychotic (haloperidol), an atypical antipsychotic (olanzapine), or placebo. We identified differentially expressed genes in three cell populations identified from the single-cell RNA-sequencing (medium spiny neurons [MSNs], microglia, and astrocytes) and applied multiple analysis pipelines to contextualize these findings, including comparison to GWAS results for schizophrenia. In MSNs in particular, differential expression analysis showed that there was a larger share of differentially expressed genes (DEGs) from mice treated with olanzapine compared with haloperidol. DEGs were enriched in loci implicated by genetic studies of schizophrenia, and we highlighted nine genes with convergent evidence. Pathway analyses of gene expression in MSNs highlighted neuron/synapse development, alternative splicing, and mitochondrial function as particularly engaged by antipsychotics. In microglia, we identified pathways involved in microglial activation and inflammation as part of the antipsychotic response. In conclusion, single-cell RNA sequencing may provide important insights into antipsychotic mechanisms of action and links to findings from psychiatric genomic studies.

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Fig. 1: Experimental overview and major cell type assignments.
Fig. 2: Differential gene expression in MSNs after chronic antipsychotic exposure.
Fig. 3: Differential gene expression in microglia after chronic antipsychotic exposure.
Fig. 4: A data reduction strategy was applied to the Hypergeometric gene-set analysis of upregulated DEG gene-sets in MSNs after chronic olanzapine exposure.
Fig. 5: GSEA pathway analysis.

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Data availability

These data have been deposited in GEO under accession GSE171977.

Code availability

Code for differential gene expression analysis have been deposited to Github and will be made available upon request.

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Acknowledgements

We thank Dr. Jens Hjerling-Leffler for assistance with experimental design and analysis, Dr. James Crowley for technical assistance, and Sydney Clarkin and Maureen Eberle for literature evaluation support. Thanks to the Translational Genomics Laboratory at the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill.

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Author notes

  1. These authors contributed equally: Anthony Abrantes, Paola Giusti-Rodriguez, Patrick F. Sullivan, Rainbo Hultman.

Authors and Affiliations

  1. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA

    Anthony Abrantes

  2. Department of Psychiatry, University of Florida, Gainesville, FL, USA

    Paola Giusti-Rodriguez

  3. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    NaEshia Ancalade, Shadia Sekle & Patrick F. Sullivan

  4. Neuroscience Center, University of North Carolina, Chapel Hill, NC, USA

    Marcus L. Basiri

  5. Center for the Neurobiology of Addiction, Pain, and Emotion, University of Washington, Seattle, WA, USA

    Garret D. Stuber

  6. Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    Patrick F. Sullivan

  7. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Patrick F. Sullivan

  8. Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, IA, USA

    Rainbo Hultman

  9. Department of Psychiatry, University of Iowa, Iowa City, IA, USA

    Rainbo Hultman

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Contributions

PGR, NA, MLB, GDS, PFS and RH designed experiments. NA, SS, and RH performed experiments. AA and PFS performed data analysis. AA, PGR, PFS, and RH interpreted the data and wrote the paper.

Corresponding author

Correspondence to Rainbo Hultman.

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Competing interests

Dr. Sullivan reports the following potentially competing financial interests: Lundbeck A/G (advisory committee, grant recipient) and Neumora (advisory committee, shareholder). Dr. Hultman reported no biomedical financial interests or potential conflicts of interest. Dr. Stuber reported no biomedical financial interests or potential conflicts of interest. Dr. Basiri reported no biomedical financial interests or potential conflicts of interest. Ms. Sekle reported no biomedical financial interests or potential conflicts of interest. Ms. Ancalade reported no biomedical financial interests or potential conflicts of interest. Dr. Giusti-Rodriguez reported no biomedical financial interests or potential conflicts of interest. Mr. Abrantes reported no biomedical financial interests or potential conflicts of interest.

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Abrantes, A., Giusti-Rodriguez, P., Ancalade, N. et al. Gene expression changes following chronic antipsychotic exposure in single cells from mouse striatum. Mol Psychiatry 27, 2803–2812 (2022). https://doi.org/10.1038/s41380-022-01509-7

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