Hippocampal transcriptome profiling in a 22q11.2 deletion syndrome mouse model: comparison with human schizophrenia.

Overview

1. Laboratory for Advanced Brain Functions, Institute for Protein Research, The University of Osaka, Suita, Osaka Japan
2. Department of Frontier Biosciences, Graduate School of Frontier Biosciences, The University of Osaka, Suita, Osaka Japan

Abstract

22q11.2 deletion syndrome (22q11.2DS) confers one of the highest genetic risks for schizophrenia, yet the molecular mechanisms remain incompletely understood. We performed comprehensive RNA sequencing of the dorsal hippocampus in Df1/+ mice, a 22q11.2DS model, integrating behavioral assessment and cross-species comparison with human schizophrenia postmortem data. Df1/+ mice exhibited selective contextual fear memory impairment without gross locomotor deficits. Transcriptomic analysis using integrated over-representation and gene set enrichment approaches revealed upregulation of synaptic signaling pathways, including glutamatergic and GABAergic neurotransmission, alongside downregulation of translational machinery and ribosomal proteins. Top upregulated pathways included “regulation of postsynaptic membrane potential” and “postsynapse organization,” featuring glutamatergic receptors, voltage-gated channels, and synaptic adhesion molecules. Downregulated pathways centered on protein synthesis, including cytoplasmic translation and ribosome biogenesis. Cross-species comparison with human schizophrenia hippocampus revealed limited but directionally consistent gene-level overlap, with 21 of 23 shared differentially expressed genes showing concordant regulation. “Regulation of postsynaptic membrane potential” was the pathway significantly enriched across both species and analytical methods, encompassing both excitatory and inhibitory receptor subunits and synaptic regulators. Concordantly downregulated genes spanned glial markers and extracellular matrix components. These findings reveal a molecular signature of enhanced synaptic gene expression coupled with reduced translational capacity and glial support, with cross-species correspondence supporting the model’s translational relevance and highlighting excitatory-inhibitory imbalance as a shared mechanism in hippocampal dysfunction underlying schizophrenia.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13041-026-01300-7.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• figshare:32330660, at figshare; found in DataCite
• figshare:32330663, at figshare; found in DataCite
• figshare:32330666, at figshare; found in DataCite
• figshare:32330669, at figshare; found in DataCite
• figshare:32330672, at figshare; found in DataCite
• geo:GSE138082, at NCBI GEO; found in the text, “Cross-species comparison with human…”
• portal.brain-map.org/atlases-and-data/rnaseq, at Allen Brain Map; found in the text, “Cell-type analysis”

Data availability

The raw and processed RNA-seq data generated in this study have been deposited in the DNA Data Bank of Japan (DDBJ) under accession number PRJDB39695. Human schizophrenia hippocampaldata were obtained from GEO (accession number: GSE138082 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE138082)). All other data supporting the findings of this study are available within the paper and its Additional Files. Source code for DE score calculation and analytical pipelines are available upon request from the corresponding author.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 28 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 3 authors, 6 keywords, 17 MeSH terms, 3 funders, 107 references, 3 RRIDs.

Cite

This paper

Yonemaru, H., Ozawa, T., & Hikida, T. (2026). Hippocampal transcriptome profiling in a 22q11.2 deletion syndrome mouse model: comparison with human schizophrenia. Molecular brain, 19(1), 41. https://doi.org/10.1186/s13041-026-01300-7

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